Compositions and Uses Thereof

ABSTRACT

Provided are solid dispersions, solid molecular complexes, salts and crystalline polymorphs involving propane- 1 -sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide.

FIELD OF THE INVENTION

Disclosed are compositions that include compounds, such as biologicallyactive compounds, and methods of making such compositions.

BACKGROUND OF THE INVENTION

PCT Application Publication Number WO 2007/002325 disclosespropane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(see e.g., page 80 and corresponding formula on page 82).

SUMMARY OF THE INVENTION

The present inventions provide compositions that include or relate toCompound I. “Compound I” as used herein means propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(the compound has also been referred to using the nomenclature“propane-1-sulfonic acid{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-2,4-difluoro-phenyl]-amide}”),salts of such compound (including pharmaceutically acceptable salts),conjugates of such compound, derivatives of such compound, forms of suchcompound, and prodrugs of such compound. The structure ofpropane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideis shown below.

propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide

As used herein, the term “solid dispersion” means any solid compositionhaving at least two components. In certain embodiments, a soliddispersion as disclosed herein includes an active ingredient (forexample Compound 1); preferably dispersed among at least one othercomponent, for example a polymer. In certain embodiments, a soliddispersion as disclosed herein is a pharmaceutical dispersion thatincludes at least one pharmaceutically or biologically active ingredient(for example Compound 1). In some embodiments, a solid dispersionincludes Compound I molecularly dispersed with a polymer. Preferably thesolid dispersion exists as a one phase system. An especially preferredsolid dispersion according to the present invention is microprecipitatedbulk powder (MBP) comprising Compound I.

The term “molecularly dispersed”, as used herein, refers to the randomdistribution of a compound (e.g., Compound I) with a polymer. In certainembodiments the compound is present in the polymer in a final state ofsubdivision. See, e.g., M. G. Vachon et al., J. Microencapsulation,14:281-301 (1997) and Vandelli et al., J. Microencapsulation, 10: 55-65(1993). In some embodiments, a compound (for example, Compound I) may bedispersed within a matrix formed by the polymer in its solid state suchthat the compound is immobilized in its amorphous form. Whether acompound is molecularly dispersed in a polymer may be evidenced in avariety of ways, e.g., by the resulting solid molecular complex having asingle glass transition temperature.

The term “solid molecular complex” as used herein means a soliddispersion that includes Compound I molecularly dispersed within apolymer matrix.

The term “immobilize”, as used herein with reference to theimmobilization of the active compound in the polymer matrix, means thatmolecules of the compound interact with molecules of the polymer in sucha way that the molecules of the compound are held in the aforementionedmatrix and prevented from crystal nucleation due to lack of mobility. Insome embodiments the polymer may prevent intermolecular hydrogen bondingor weak dispersion forces between two or more drug molecules of CompoundI. See, for example, Matsumoro and Zografi, Pharmaceutical Research, Vo.16, No. 11, p 1722-1728, 1999.

Accordingly, in a first aspect, provided is a solid dispersion thatincludes Compound I and a polymer. Also provided is a solid molecularcomplex that includes Compound I and a polymer. The polymer may be anon-ionic polymer or an ionic polymer. In certain embodiments, thepolymer is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl cellulose, methacrylicacid copolymers, and the like, as well as mixtures of any two or morethereof. In some embodiments the ratio of the amount by weight ofCompound I within the solid dispersion or solid molecular complex to theamount by weight of the ionic polymer therein is from about 1:9 to about5:5. In a preferred embodiment of the invention, the ratio of the amountby weight of Compound I within the solid dispersion or solid molecularcomplex to the amount by weight of the ionic polymer therein is fromabout 2:8 to about 4:6. In various embodiments the ratio of Compound Itothe polymer in the solid dispersion is not 1:1; for example the ratiomay be about 2:8; or about 3:7; or about 4:6. In a preferred embodiment,the ratio of the amount by weight of Compound I within the soliddispersion or solid molecular complex to the amount by weight of theionic polymer therein is about 3:7. In certain preferred embodimentsCompound I may be present in the solid dispersion in an amount of fromabout 0.1% to about 80%, by weight, of the solid dispersion; or inamount of from about 10% to about 70%, by weight, of the soliddispersion; or in an amount of from about 20% to about 60%, by weight,of the solid dispersion; or in an amount of from about 20% to about 40%,by weight, of the solid dispersion; or in an amount of about 30%, byweight, of the solid dispersion. In certain embodiments of the soliddispersions, the polymer may be present in the solid dispersion in anamount of not less than about 20%, by weight, of the solid dispersion;or in an amount of from about 20% to about 95% by weight of the soliddispersion; or in an amount of from about 20% to about 70% by weight ofthe solid dispersion.

In certain preferred embodiments Compound I is stable in the soliddispersion (or solid molecular complex) for at least 2 months at 25° C.;or for at least 6 months at 25° C.; or for at least 12 months at 25° C.;or for at least 15 months at 25° C.; or for at least 18 months at 25°C.; or for at least 24 months at 25° C.; or for at least 2 months at 40°C. and 75% relative humidity; or for at least 4 months at 40° C. and 75%relative humidity; or for at least 5 months at 40° C. and 75% relativehumidity; or for at least 6 months at 40° C. and 75% relative humidity.In certain preferred embodiments, Compound I is immobilized so that itis primarily in amorphous form within the solid dispersion or solidmolecular complex for at least three weeks of storage at 40° C. and 75%relative humidity; or for at least one month of storage at 40° C. and75% relative humidity; or for at least two months of storage at 40° C.and 75% relative humidity; or for at least three months of storage at40° C. and 75% relative humidity; or for at least four months of storageat 40° C. and 75% relative humidity; or for at least five months ofstorage at 40° C. and 75% relative humidity; or for at least six monthsof storage at 40° C. and 75% relative humidity.

In some embodiments, Compound I is present in the complex as a tosylatesalt; or as a mesylate salt. The complex may further include apharmaceutically acceptable carrier.

As used herein, the term “primarily in amorphous form” means thatgreater than 50%; or greater than 55%; or greater than 60%; or greaterthan 65%; or greater than 70%; or greater than 75%; or greater than 80%;or greater than 85%; or greater than 90%; or greater than 95% of thecompound present in a composition is in amorphous form.

As used herein, the term “about” used in the context of quantitativemeasurements means the indicated amount ±10%. For example, “about 2:8”would mean 1.8-2.2:7.2-8.8.

As used herein in the context of a pharmaceutically or biologicallyactive compound (for example Compound I), the term “stable” refers tothe ability of the compound to retain its activity or to retain certainphysical or chemical properties under certain specified conditions. Insome embodiments, an active compound is “stable” if the activity at theend of the specified period is at least 50%; or at least 60%; or atleast 70%; or at least 75%; or at least 80%; or at least 85%; or atleast 90%; or at least 95%; or at least 98% of the activity of thecompound at the beginning of the specified period. In some embodiments,a compound in an amorphous form is stable if at least 50%; or at least60%; or at least 70%; or at least 75%; or at least 80%; or at least 85%;or at least 90%; or at least 95%; or at least 98% of the compoundremains in the amorphous form at the end of the specified period. Infurther embodiments, an amorphous compound is stable if it does not formany detectable crystalline peaks in powder XRD profiles during theindicated period.

The term “methacrylic acid copolymers” as used herein includesmethacrylic acid copolymers, methacrylic acid-methacrylate copolymers,methacrylic acid-ethyl acrylate copolymers, ammonium methacrylatecopolymers, aminoalkyl methacrylate copolymers and the like. In certainembodiments, a “methacrylic acid copolymer” may be EUDRAGIT® L 100 andEUDRAGIT® L 12,5 (also referred to as, or conforms with: “MethacrylicAcid Copolymer, Type A;” “Methacrylic Acid-Methyl Methacrylate Copolymer(1:1);” “Methacrylic Acid Copolymer L;” “DMF 1242” or “PR-MF 6918”);EUDRAGIT® S 100 and EUDRAGIT® S 12,5 (also referred to as, or conformswith: “Methacrylic Acid Copolymer, Type B;” “Methacrylic Acid-MethylMethacrylate Copolymer (1:2);” “Methacrylic Acid Copolymer S;” “DMF1242” or “PR-MF 6918”); EUDRAGIT® L 100-55 (also referred to as, orconforms with: “Methacrylic Acid Copolymer, Type C;” “MethacrylicAcid-Ethyl Acrylate Copolymer (1:1) Type A;” “Dried Methacrylic AcidCopolymer LD;” or “DMF 2584”); EUDRAGIT® L 30 D-55 (also referred to as,or conforms with: “Methacrylic Acid Copolymer Dispersion;” “MethacrylicAcid-Ethyl Acrylate Copolymer (1:1) Dispersion 30 Per Cent;”“Methacrylic Acid Copolymer LD;” JPE DMF 2584; PR-MF 8216); EUDRAGIT®FS30 D (also referred to as DMF 13941 or DMF 2006-176); EUDRAGIT® RL 100(also referred to as, or conforms with: “Ammonio Methacrylate Copolymer,Type A;” “Ammonio Methacrylate Copolymer (Type A);” “AminoalkylMethacrylate Copolymer RS;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® RL PO(also referred to as, or conforms with: “Ammonio Methacrylate Copolymer,Type A;” “Ammonio Methacrylate Copolymer (Type A);” “AminoalkylMethacrylate Copolymer RS;” “DMF 1242”); EUDRAGIT® RL 12,5 (alsoreferred to as, or conforms with “Ammonio Methacrylate Copolymer, TypeA;” “Ammonio Methacrylate Copolymer (Type A);” “DMF 1242” or “PR-MF6918”); EUDRAGIT® L 100-55 (also referred to as, or conforms with:“Methacrylic Acid Copolymer, Type C;” “Methacrylic Acid-Ethyl AcrylateCopolymer (1:1) Type A;” “Dried Methacrylic Acid Copolymer LD;” “DMF2584”); EUDRAGIT® L 30 D-55 (also referred to as, or conforms with:“Methacrylic Acid Copolymer Dispersion” NF “Methacrylic Acid-EthylAcrylate Copolymer (1:1) Dispersion 30 Per Cent;” “Methacrylic AcidCopolymer LD;” “DMF 2584” or “PR-MF 8216”); EUDRAGIT®FS 30 D (alsoreferred to as, or conforms with: “DMF 13941” or “DMF 2006-176”);EUDRAGIT® RL 100 (also referred to as, or conforms with: “AmmonioMethacrylate Copolymer, Type A;” “Ammonio Methacrylate Copolymer (TypeA);” “Aminoalkyl Methacrylate Copolymer RS;” “DMF 1242;” or “PR-MF6918”); EUDRAGIT® RL PO (also referred to as, or conforms with: “AmmonioMethacrylate Copolymer, Type A;” “Ammonio Methacrylate Copolymer (TypeA);” “Aminoalkyl Methacrylate Copolymer RS;” or “DMF 1242”); EUDRAGIT®RL 12,5 (also referred to as, or conforms with: polymer conforms to“Ammonio Methacrylate Copolymer, Type A;” “Ammonio MethacrylateCopolymer (Type A);” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® RL 30 D(also referred to as, or conforms with: “Ammonio Methacrylate CopolymerDispersion, Type A;” “Ammonio Methacrylate Copolymer (Type A);” or “DMF1242”); EUDRAGIT® RS 100 (also referred to as, or conforms with:“Ammonio Methacrylate Copolymer, Type B;” NF “Ammonio MethacrylateCopolymer (Type B);” “Aminoalkyl Methacrylate Copolymer RS;” “DMF 1242”or “PR-MF 6918”); EUDRAGIT®RS PO (also referred to as, or conforms with:“Ammonio Methacrylate Copolymer, Type B;” “Ammonio MethacrylateCopolymer (Type B);” “Aminoalkyl Methacrylate Copolymer RS;” or “DMF1242”); EUDRAGIT® RS 12,5 (also referred to as, or conforms with:“Ammonio Methacrylate Copolymer, Type B;” NF polymer conforms to“Ammonio Methacrylate Copolymer (Type Br “DMF 1242” or “PR-MF 6918”);EUDRAGIT® RS 30 D (also referred to as, or conforms with: “AmmonioMethacrylate Copolymer Dispersion, Type B;” NF polymer conforms to“Ammonio Methacrylate Copolymer (Type B);” or “DMF 1242”); EUDRAGIT® E100 (also referred to as, or conforms with: “Amino MethacrylateCopolymer;” NF “Basic Butylated Methacrylate Copolymer;” “AminoalkylMethacrylate Copolymer E;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® E PO(also referred to as, or conforms with: “Basic Butylated MethacrylateCopolymer;” “Aminoalkyl Methacrylate Copolymer E;” “Amino MethacrylateCopolymer;” “DMF 1242”); EUDRAGIT® E 12,5 (also referred to as, orconforms with: “Amino Methacrylate Copolymer;” “Basic ButylatedMethacrylate Copolymer;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® NE 30 D(also referred to as, or conforms with: “Ethyl Acrylate and MethylMethacrylate Copolymer Dispersion;” “Polyacrylate Dispersion 30 PerCent;” (“Poly(ethylacrylat-methylmethacrylat)-Dispersion 30%”); “EthylAcrylate Methyl Methacrylate Copolymer Dispersion;” “DMF 2822” or “PR-MF6918”); EUDRAGIT® NE 40 D (also referred to as, or conforms with: DMF2822); EUDRAGIT® NM 30 D (also referred to as “Polyacrylate Dispersion30 Per Cent;” “(Poly(ethylacrylat-methylmethacrylat)-Dispersion 30%);”or “DMF 2822”; PLASTOID® B (also referred to as, or conforms with: “DMF12102”), or the like.

In a second aspect, provided are methods of making solid dispersions orsolid molecular complexes as disclosed herein. The method may involveusing Compound. I in the form of a tosylate or mesylate salt.

In a third aspect, provided is a crystalline polymorph Form 1 ofCompound I. In certain embodiments the crystalline polymorph Form 1 ofCompound I exhibits a powder x-ray diffraction pattern havingcharacteristic peak locations of approximately 4.7, 9.4, 11.0, 12.5, and15.4 degrees 2θ; or having characteristic peak locations ofapproximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 18.6, and 22.2degrees 2θ; or having characteristic peak locations of approximately4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 16.1, 18.6, 19.0, 22.2 and 26.8degrees 2θ. In certain embodiments the crystalline polymorph Form 1 ofCompound I exhibits a powder x-ray diffraction pattern substantially thesame as the powder x-ray diffraction pattern of FIG. 1. Also providedare methods of preparing solid dispersions and solid molecular complexesas described herein wherein the solid dispersion or solid molecularcomplex is prepared from Compound I in the form of crystalline polymorphForm 1.

In a fourth aspect, provided is a crystalline polymorph Form 2 ofCompound I. In certain embodiments the crystalline polymorph Form 2 ofCompound I exhibits a powder x-ray diffraction pattern havingcharacteristic peak locations of approximately 8.8, 9.2, 13.5, 19.1 and24.4 degrees 2θ; or having characteristic peak locations ofapproximately 6.7, 8.8, 9.2, 13.5, 15.0, 17.7, 19.1, 19.7, 21.4 and 24.4degrees 2θ; or having characteristic peak locations of approximately6.7, 8.8, 9.2, 13.5, 14.1, 14.5, 15.0, 16.2, 17.0, 17.7, 19.1, 19.7,21.4, 22.2, 24.1, 24.4, and 28.1 degrees 2θ. In certain embodiments thecrystalline polymorph Form 2 of Compound I exhibits a powder x-raydiffraction pattern substantially the same as the powder x-raydiffraction pattern of FIG. 2. Also provided are methods of preparingsolid dispersions and solid molecular complexes as described hereinwherein the solid dispersion or solid molecular complex is prepared fromCompound I in the form of crystalline polymorph Form 2.

All atoms within the compound described herein are intended to includeany isotope thereof, unless clearly indicated to the contrary. It isunderstood that for any given atom, the isotopes may be presentessentially in ratios according to their natural occurrence, or one ormore particular atoms may be enhanced with respect to one or moreisotopes using synthetic methods known to one skilled in the art. Thus,hydrogen includes for example ¹H, ²H, ³H; carbon includes for example¹¹C, ¹²C, ¹³C, ¹⁴C; oxygen includes for example ¹⁶O, ¹⁷O, ¹⁸O; nitrogenincludes for example ¹³N, ¹⁴N, ¹⁵N; sulfur includes for example ³²S,³³S, ³⁴S, ³⁵S, ³⁶S, ³⁷S, ³⁸S; fluoro includes for example ¹⁷F, ¹⁸F, ¹⁹F;chloro includes for example ³⁵Cl, ³⁶Cl, ³⁷Cl, ³⁸Cl, ³⁹Cl; and the like.

As used herein, the term “solid form” refers to a solid preparation(i.e. a preparation that is neither gas nor liquid) of apharmaceutically active compound that is suitable for administration toan intended animal subject for therapeutic purposes. The solid formincludes any complex, such as a salt, co-crystal or an amorphouscomplex, as well as any polymorph of the compound. The solid form may besubstantially crystalline, semi-crystalline or substantially amorphous.The solid form may be administered directly or used in the preparationof a suitable composition having improved pharmaceutical properties. Forexample, the solid form may be used in a formulation comprising at leastone pharmaceutically acceptable carrier or excipient.

As used herein, the term “substantially crystalline” material embracesmaterial which has greater than about 90% crystallinity; and“crystalline” material embraces material which has greater than about98% crystallinity.

As used herein, the term “substantially amorphous” material embracesmaterial which has no more than about 10% crystallinity; and “amorphous”material embraces material which has no more than about 2%crystallinity.

As used herein, the term “semi-crystalline” material embraces materialwhich is greater than 10% crystallinity, but no greater than 90%crystallinity; preferably “semi-crystalline” material embraces materialwhich is greater than 20% crystallinity, but no greater than 80%crystallinity. In one aspect of the present invention, a mixture ofsolid forms of a compound may be prepared, for example, a mixture ofamorphous and crystalline solid forms, e.g. to provide a“semi-crystalline” solid form. Such a “semi-crystalline” solid form maybe prepared by methods known in the art, for example by mixing anamorphous solid form with a crystalline solid form in the desired ratio.In some instances, a compound mixed with acid or base forms an amorphouscomplex; a semi-crystalline solid can be prepared employing an amount ofcompound component in excess of the stoichiometry of the compound andacid or base in the amorphous complex, thereby resulting in an amount ofthe amorphous complex that is based on the stoichiometry thereof, withexcess compound in a crystalline form. The amount of excess compoundused in the preparation of the complex can be adjusted to provide thedesired ratio of amorphous complex to crystalline compound in theresulting mixture of solid forms. For example, where the amorphouscomplex of acid or base and compound has a 1:1 stoichiometry, preparingsaid complex with a 2:1 mole ratio of compound to acid or base willresult in a solid form of 50% amorphous complex and 50% crystallinecompound. Such a mixture of solid forms may be beneficial as a drugproduct, for example, by providing an amorphous component havingimproved biopharmaceutical properties along with the crystallinecomponent. The amorphous component would be more readily bioavailablewhile the crystalline component would have a delayed bioavailability.Such a mixture may provide both rapid and extended exposure to theactive compound.

As used herein, the term “complex” refers to a combination of apharmaceutically active compound and an additional molecular speciesthat forms or produces a new chemical species in a solid form. In someinstances, the complex may be a salt, i.e. where the additionalmolecular species provides an acid/base counter ion to an acid/basegroup of the compound resulting in an acid:base interaction that forms atypical salt. While such salt forms are typically substantiallycrystalline, they can also be partially crystalline, substantiallyamorphous, or amorphous forms. In some instances, the additionalmolecular species, in combination with the pharmaceutically activecompound, forms a non-salt co-crystal, i.e. the compound and molecularspecies do not interact by way of a typical acid:base interaction, butstill form a substantially crystalline structure. Co-crystals may alsobe formed from a salt of the compound and an additional molecularspecies. In some instances, the complex is a substantially amorphouscomplex, which may contain salt-like acid:base interactions that do notform typical salt crystals, but instead form a substantially amorphoussolid, i.e. a solid whose X-ray powder diffraction pattern exhibits nosharp peaks (e.g. exhibits an amorphous halo).

As used herein, the term “stoichiometry” refers to the molar ratio oftwo or more reactants that combine to form a complex, for example, themolar ratio of acid or base to compound that form an amorphous complex.For example, a 1:1 mixture of acid or base with compound (i.e. 1 moleacid or base per mole of compound) resulting in an amorphous solid formhas a 1:1 stoichiometry.

As used herein, the term “composition” refers to a pharmaceuticalpreparation suitable for administration to an intended animal subjectfor therapeutic purposes that contains at least one pharmaceuticallyactive compound, including any solid form thereof. The composition mayinclude at least one additional pharmaceutically acceptable component toprovide an improved formulation of the compound, such as a suitablecarrier or excipient.

The term “pharmaceutically acceptable” indicates that the indicatedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectibles.

In the present context, the term “therapeutically effective” or“effective amount” indicates that the materials or amount of material iseffective to prevent, alleviate, or ameliorate one or more symptoms of adisease or medical condition, and/or to prolong the survival of thesubject being treated. In certain embodiments, a“therapeutically-effective amount” of Compound I refers to such dosagesand/or administration for such periods of time necessary to inhibithuman b-Raf containing the V600E mutation. Moreover, a therapeuticallyeffective amount may be one in which the overalltherapeutically-beneficial effects outweigh the toxic or undesirableside effects. A therapeutically-effective amount of Compound I mayvaries according to disease state, age and weight of the subject beingtreated. Thus, dosage regimens are typically adjusted to the individualrequirements in each particular case and are within the skill in theart. In certain embodiments, an appropriate daily dose foradministration of Compound I to an adult human may be from about 100 mgto about 3200 mg; or from about 250 mg to about 2000 mg, although theupper limit may be exceeded when indicated. A daily dosage of Compound Ican be administered as a single dose, in divided doses, or, forparenteral administration, it may be given as subcutaneous injection.

In the present context, the terms “synergistically effective” or“synergistic effect” indicate that two or more compounds that aretherapeutically effective, when used in combination, provide improvedtherapeutic effects greater than the additive effect that would beexpected based on the effect of each compound used by itself.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with a particular biomolecule such as a protein kinase. Forexample, an agonist or antagonist of a particular biomolecule modulatesthe activity of that biomolecule, e.g., an enzyme, by either increasing(e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor)the activity of the biomolecule, such as an enzyme. Such activity istypically indicated in terms of an inhibitory concentration (IC₅₀) orexcitation concentration (EC₅₀) of the compound for an inhibitor oractivator, respectively, with respect to, for example, an enzyme.

Additional aspects and embodiments will be apparent from the followingDetailed Description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder x-ray diffraction pattern for the crystallinepolymorph Form 1 of Compound I.

FIG. 2 is a powder x-ray diffraction pattern for the crystallinepolymorph Form 2 of Compound I.

FIG. 3 is a comparison of powder x-ray diffraction pattern for thecrystalline polymorph Form 2 and the mesylate salt of Compound I.

FIG. 4 is a comparison of powder x-ray diffraction pattern for thecrystalline polymorph Form 2 and the tosylate salt of Compound I.

FIG. 5 is a schematic drawing of an exemplary setup for manufacturing asolid dispersion (MBP) according to steps a) to d), more specificallyaccording to Example 22 of the present invention.

FIG. 6 is a detailed schematic drawing of the high shear mixing unit((6) of FIG. 5).

FIGS. 7A and 7B provide a comparison of X-ray patterns obtained from twolots of solid dispersions (MBP's) containing HPMCAS and Compound I,manufactured via high shear mixer precipitation according to the methoddisclosed in Example 22 (see FIG. 7A) and via conventional sprayprecipitation (see FIG. 7B).

DETAILED DESCRIPTION

Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide,is a compound with the following structure:

Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(Compound I)

In some embodiments, Compound I is a b-raf kinase inhibitor. Normallyfunctioning b-Raf is a kinase which is involved in the relay of signalsfrom the cell membrane to the nucleus and is active only when it isneeded to relay such signals. Mutant b-Raf, however, is constantlyactive and thus plays a role in tumor development. Mutant b-Rafcontaining a V600E mutation has been implicated in various tumors, forexample, colorectal cancer, melanoma, and thyroid cancer.Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidespecifically targets mutant b-Raf containing the V600E mutation.Accordingly, such an inhibitor is used in the inhibition of tumors,particularly solid tumors such as melanoma. As previously stated, thephrase “Compound I”, as used herein, will refer to propane-1-sulfonicacid{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-2,4-difluoro-phenyl]-amideas well as any salt, conjugate, derivative, or prodrug thereof.

Compounds that have low solubility in water (for example, certaincompounds in crystalline form), have a low dissolution rate and as aresult can exhibit poor bioavailability. Poorly bioavailable compoundscan present problems for therapeutic administration to a patient, oftendue to unpredictability in dose/therapy effects caused by erraticabsorption of the compound by the patient. For example, the intake offood may affect the ability of the patient to absorb such poorlybioavailable compounds, thus potentially requiring dosing regimens totake into account the effect of food. In addition, when dosing, a largesafety margin may be required for the dose as a result of theunpredictable dose effects. Further, due to poor bioavailability, alarge dose of the compound may be required to achieve a desiredtherapeutic effect, thus potentially resulting in undesired sideeffects.

Amorphous forms of Compound I have improved solubility in water ascompared to the crystalline form, but is unstable as it has a tendencyto crystallize. Thus it is desired to formulate Compound I so that itmay stably exist primarily in amorphous form.

Thus, in some aspects and embodiments disclosed and described herein,techniques, methods and compositions for improving the solubility and/orbioavailability of Compound I are provided. In certain embodiments,provided are compositions and methods involving Compound I in acomposition, form, or formulation in which it has improved watersolubility and/or bioavailability of as compared to Compound I in acrystalline form, or Compound I in a primarily crystalline form.

In some embodiments provided are compositions including Compound I in anamorphous form of the compound. The amorphous form of Compound I mayhave improved solubility in water as compared to Compound I in acrystalline form. In certain embodiments, formulations of Compound I inwhich Compound I exists stably in amorphous form may be accomplished,for example, by immobilizing the compound within a matrix formed by apolymer. See, for example, U.S. Pat. No. 6,350,786.

Solid Dispersions and Solid Molecular Complexes of Compound I and aPolymer

In some aspects and embodiments provided are solid dispersions and solidmolecular complexes that include Compound I. For example, Compound I maybe dispersed within a matrix formed by a polymer in its solid state suchthat it is immobilized in its amorphous form. In some embodiments thepolymer may prevent intramolecular hydrogen bonding or weak dispersionforces between two or more drug molecules of Compound I. See, forexample, Matsumoro and Zografi, Pharmaceutical Research, Vo. 16, No. 11,p 1722-1728, 1999. In certain embodiments, the solid dispersion providesfor a large surface area, thus further allowing for improved dissolutionand bioavailability of Compound I. In certain embodiments a soliddispersion or solid molecular complex includes atherapeutically-effective amount of Compound I.

In some embodiments of the present inventions, Compound I is present inthe solid dispersion in an amount of from about 1% to about 50%, byweight; or from about 10% to about 40% by weight; or from about 20% toabout 35% by weight; or from about 25% to about 30% by weight. Inrelated embodiments, a polymer is present in the solid dispersion in anamount of from about 0% to about 50% by weight; or from about 5% toabout 60% by weight; or from 10% to about 70% by weight. In certainembodiments a polymer is present in the solid dispersion in an amountgreater than about 10% by weight; or greater than about 20% by weight;or greater than about 30% by weight; or greater than about 40% byweight; or greater than about 50% by weight. In one preferredembodiment, the solid dispersion is about 30% by weight Compound I andabout 70% by weight polymer.

The solid dispersion may comprise Compound I dispersed in a non-ionicpolymer. This may be accomplished by various means, including: (A)melting the polymer and dissolving the compound in the polymer and thencooling the mixture; and (B) dissolving both the compound of interestand the polymer in an organic solvent and evaporating the solvent in arotary evaporator, for example. The resulting solid dispersion maycomprise the compound dispersed in the polymer in amorphous form.

A solid dispersion may be formed by dispersing Compound I in an ionicpolymer. Such solid dispersion may result in increased stability ofCompound I. This may be accomplished by various means, including themethods described above for use in forming a dispersion in a non-ionicpolymer. Because ionic polymers have pH dependent solubility in aqueoussystems, the resulting solid dispersion of the Compound I and thepolymer may be stable at low pH in the stomach and release the CompoundI in the intestine at higher pH which is the site of absorption. Inpreferred embodiments, Compound I in such solid dispersions with anionic polymer may thus be less capable of separating from the polymerand may be immobilized by the polymer in its amorphous form. Any ionicpolymer may be used in the practice of the present invention. Examplesof such ionic polymers include hydroxypropylmethyl cellulose acetatesuccinate (HPMC-AS), hydroxypropylmethyl cellulose phthalate (HPMCP),and methacrylic acid copolymers. Because one purpose of formulatingCompound I in a complex with an ionic polymer is to allow for CompoundIto be immobilized so that it exists primarily in amorphous form, apolymer which is capable of immobilizing Compound I so that it existsprimarily in an amorphous form for an extended period of time ispreferred. It has been found that polymers such as HPMC-AS and Eudragit®L 100-55 (a methacrylic acid copolymer) are capable of immobilizingCompound I so that it exists primarily in an amorphous form for at leastfour weeks while in storage at 40° C. and 75% relative humidity. Assuch, HPMC-AS and Eudragit® L 100-55 are preferred polymers for use incertain embodiments of the present invention.

HPMC-AS (HPMCAS or AQOAT™, which is available from, for example,Shin-Etsu) is a particularly preferred polymer for use in the practiceof certain embodiments of the present invention. It is available in thefollowing grades: AS-LF, AS-MF, AS-HF, AS-LG, AS-MG and AS-HG. HPMC-ASis an anionic, relatively water insoluble, high molecular weight polymerwith a pH dependent water solubility, leading to dissolution at pH 5.2and above. Said dissolution can be tailored between pH 5.2 and 6.5according to the HPMC-AS grades used. HPMC-AS may be relativelyresistant to breakdown in the acidic environment of the stomach andunder normal temperatures of storage. At the same time, because HPMC-ASdissolves at pH 5.2 and above, it dissolves in the basic environment ofthe intestine, thus allowing for improved absorption of Compound I andfurther allowing for improved bioavailability of the Compound I.Accordingly, in certain embodiments of the invention, Compound I is in asolid dispersion with at least one polymer selected from HPMC-AS gradesas mentioned above. It is, however, contemplated that a mixture of twoor more of the various HPMC-AS grades can also be used in accordancewith the present invention.

In an embodiment of the invention, the ratio of the amount by weight ofCompound I within the solid complex to the amount by weight of the ionicpolymer therein is from about 1:9 to about 1:1. In a preferredembodiment of the invention, the ratio of the amount by weight ofCompound I within the solid complex to the amount by weight of the ionicpolymer therein is from about 2:8 to about 4:6. In a preferredembodiment of the invention, the ratio of the amount by weight ofCompound I within the solid complex to the amount by weight of the ionicpolymer therein is about 3:7.

In an embodiment of the present invention, Compound I is immobilized sothat it is primarily in amorphous form within the complex for up tothree weeks of storage at 40° C. and 75% relative humidity. In apreferred embodiment, Compound I is immobilized so that it is primarilyin amorphous form within the complex for up to one month of storage at40° C. and 75% relative humidity. In another preferred embodiment,Compound I is immobilized so that it is primarily in amorphous formwithin the complex for up to two months of storage at 40° C. and 75%relative humidity. In another preferred embodiment, Compound I isimmobilized so that it is primarily in amorphous form within the complexfor up to three months of storage at 40° C. and 75% relative humidity.

In certain embodiments, HPMC-AS is present in the solid dispersion inamount of from about 1% to about 50% by weight; or from about 5% toabout 60% by weight; or from 10% to about 70% by weight. In certainembodiments, HPMC-AS is present in the solid dispersion in an amountgreater than about 10% by weight; or greater than about 20% by weight orgreater than about 30% by weight; or greater than about 40% by weight;or greater than about 50% by weight.

The present inventions also relate to compositions comprising a soliddispersion or solid molecular complex as disclosed herein. Thecomposition may, in addition to the solid dispersion or solid molecularcomplex, also comprise therapeutically inert, inorganic or organiccarriers (for example, pharmaceutically-acceptable carriers orexcipients). The pharmaceutical composition may also contain additionalagents such as preserving agents, solubilizing agents, stabilizingagents, wetting agents, emulsifying agents, sweetening agents, coloringagents, flavoring agents, salts for varying the osmotic pressure,buffers, coating agents and antioxidants. The composition may alsocontain additional therapeutically-active compounds or more than onetherapeutically-active compound/polymer complex (e.g., a soliddispersion or solid molecular complex).

In certain embodiments, the composition includes the solid dispersion orsolid molecular complex suspended in an aqueous vehicle containinghydroxypropylcellulose (HPC). In an especially preferred embodiment, thevehicle contains about 2% by weight HPC. In a preferred embodiment, thecomposition includes colloidal silicon dioxide (silica).

In certain embodiments, the addition of colloidal silicon dioxide mayfurther improve the stability of the solid dispersion or solid molecularcomplex. In an especially preferred embodiment, the composition includesat least about 0.5% by weight colloidal silicon dioxide.

In certain embodiments provided compositions include Compound I (forexample in a solid dispersion or solid molecular complex) andCrospovidone (or Polyplasdone XL; a disintegrating agent for the dosageform), magnesium stearate (a lubricant that may be used in tablet andcapsulation operations), and/or croscarmellose sodium (AcDiSol; adisintegrating agent).

In an especially preferred embodiment, the composition comprises thesolid dispersion or solid molecular complex suspended in an aqueousvehicle that is up to 2% by weight HPC and at least about 0.5% by weightcolloidal silicon dioxide.

Method of Making a Solid Molecular Complex of Compound I and an IonicPolymer

Also provided are methods of making solid molecular complexes asdisclosed herein and compositions comprising the solid molecularcomplexes. In the method, Compound I may be microprecipitated with apolymer as disclosed herein (for example, HPMC-AS). Microprecipitationmay be accomplished by any means known in the art, for example: spraydrying or lyophilization; solvent-controlled precipitation;pH-controlled precipitation; hot melt extrusion; and supercritical fluidtechnology. Each of these methods is described in more detail below.

Once the solid dispersion precipitates out of solution using the variousmethods, it can be recovered from the solution by procedures known tothose skilled in the art, for example by filtration, centrifugation,washing, etc. The recovered solid molecular complex can then be dried(e.g., in air, an oven, or a vacuum) and the resulting solid can bemilled, pulverized or micronized to a fine powder by means known in theart. The powder form of the solid dispersion can then be dispersed in acarrier to form a pharmaceutical composition. In a preferred embodiment,at least about 0.5% w/w colloidal silicon dioxide is added to thecomposition.

a) Spray Drying or Lyophilization Process

Compound I and a polymer (for example, HPMC-AS) may be dissolved in acommon solvent having a low boiling point, e.g., ethanol, methanol,acetone, etc. By means of spray drying or lyophilization, the solvent isevaporated by flash evaporation at a temperature close to the boilingpoint thereof, or under a high vacuum (low vapor pressure), leavingCompound I precipitated in a matrix formed by the polymer. In certainembodiments Compound I is in a mesylate or tosylate salt form, and thuspreferably has improved solubility.

b) Solvent Controlled Precipitation

Compound I and a polymer (for example, HPMC-AS) may be dissolved in acommon solvent, e.g., dimethylacetamide, dimethylformamide, dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP), etc. The CompoundI/polymer solution is added to cold (0 to 7° C., preferably 2 to 5° C.)water adjusted to an appropriate pH (for example in many embodiments anappropriate pH is a pH of 3 or less). This causes Compound Itomicroprecipitate in a matrix formed by the polymer (for example,HPMC-AS). The microprecipitate may be washed several times with aqueousmedium until the residual solvent falls below an acceptable limit forthat solvent. An “acceptable limit” for each solvent is determinedpursuant to the International Conference on Harmonization (ICH)guidelines.

In a preferred embodiment, a solution comprising Compound I, an organicsolvent (such as dimethylformamide, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP), and the like) and theionic polymer is formed. The organic solvent is preferably DMA at 20 to25° C. The solution may be formed by first dissolving Compound I intothe organic solvent. Then, while stirring, the polymer is added. Themixture is then heated up to between about 50 to about 110° C.,preferably to about 70° C.

A second solution that is 0.01 N HCl is also formed. This will herein betermed the “aqueous phase”. The aqueous phase has a temperature betweenabout 0 and about 60° C., preferably between 5 and 15° C.

The aqueous phase is then circulated through the mixing chamber of ahigh shear mixer while the organic phase is dosed into the chamber whilethe chamber is operating. Dosing may be accomplished with, for example,a gear pump, a hose pump, or a syringe pump. In a preferred embodiment,dosing is accomplished using a gear pump with an injector nozzle pointedinto the mixing chamber. The mixing chamber preferably comprises a rotorand a stator. The rotor and the stator may, for example, each haveeither one or two rows of teeth. In a preferred embodiment, the rotorand the stator each have one row of teeth. The tip speed of the rotor ispreferably set at between about 15 and about 25 m/sec.

During the mixing process, Compound I and the polymer precipitate,producing a suspension of particles of the complex of Compound I and thepolymer in aqueous organic media. The suspension may then be subjectedto a number of passes through a dispersing unit in order to adjust theparticle size of the particles of the compound. The suspension may thenbe centrifuged and washed with the aqueous phase several times in orderto remove the organic solvent and then washed once with pure water. Theobtained product may then be delumped and dried to obtain the solidcomplex of the present invention. During the drying process, thetemperature of the complex is preferably below 40° C. in order to avoidrecrystallization of Compound I.

In certain more specific embodiments, the above method includes thefollowing steps,

-   -   (a) dissolution of Compound I and HPMCAS in the same organic        solvent to give one single organic phase;    -   (b) continuously adding the organic phase obtained under (a)        into an aqueous phase which is present in a mixing chamber, said        mixing chamber being equipped with a high shear mixing unit and        two additional openings which connect said mixing chamber to a        closed loop wherein said aqueous phase is circulated and passes        through the mixing chamber;    -   (c) precipitation of a mixture consisting of the amorphous form        of Compound I and HPMCAS from the aqueous phase mentioned under        (b), while the high shear mixer is operating and said aqueous        phase is passed through the mixing chamber in a closed loop,        resulting in the formation of an aqueous suspension of the        precipitate;    -   (d) continuously circulating the aqueous suspension through the        mixing chamber while the high shear mixing unit is operating and        after the organic solution prepared under (a) has been        completely added to the aqueous phase until a defined particle        size and/or particle size distribution is obtained;    -   (e) isolating the solid phase from the suspension;    -   (f) washing the isolated solid phase with water; and    -   (g) delumping and drying the solid phase.

In still more specific embodiments the present methods include thesteps, wherein

-   -   the organic phase in step (a) above is a 35% solution of        Compound I and HPMCAS in DMA, the ratio of Compound Ito HPMCAS        being 30% to 70% (w/w); and    -   the continuous adding in step (b) above is achieved via an        injector nozzle which is oriented at an angle between 40 and 50°        to the longitudinal axis of the high shear mixer and has a        distance of about 1 to about 10 mm from the rotor of said high        shear mixer which is operating with a tip speed of about 15 to        about 25 msec.

In still more specific embodiments the present methods include the step,wherein

-   -   the continuous adding in step (b) above is achieved via an        injector nozzle which is oriented at an angle of about 45° to        the longitudinal axis of the high shear mixer and has a distance        of about 2 to about 4 mm from the rotor of said high shear mixer        which is operating with a tip speed of about 25 m/sec.

In other specific embodiments the present methods include the step,wherein

-   -   the drying in step (g) above is achieved via fluidized bed        drying.

In a further embodiment there are provided the solid dispersionsobtained by the above-mentioned method.

The dried precipitate obtained by the above method can be furtherprocessed into any type of solid pharmaceutical preparations or dosageforms, which are known to the person of skill in the art. Particularlypreferred are oral dosage forms such as tablets, capsules, pills,powders, suspensions, and the like.

Consequently, so obtained pharmaceutical preparations form furtherembodiments provided herein.

The term “organic solvent” mentioned under step (a) above means anyorganic solvent wherein both Compound I and HPMCAS are miscible.Preferred organic solvents are N-Methylpyrrolidone (NMP),Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), Dimethylacetamide(DMA), and the like, with DMA being the most preferred. The combinedamount of Compound I and HPMCAS together in the organic phase can bewithin the range of about 15 to 40 weight %, preferably about 25 to 40,most preferably about 35 weight %. The weight ratio of Compound I/HPMCASin the organic solvent is about 30/70 weight %, respectively.Preferably, the temperature of the organic solvent is adjusted between50 and 110° C., preferably 60 and 90° C., most preferred at about 70° C.prior to its addition to the mixing chamber as mentioned under step (b).The mixture of Compound I and HPMCAS in the organic solvent is alsodesignated herein as the “organic phase” or “DMA phase”.

The term “aqueous phase” mentioned under step (b) preferably consists ofacidic water (pH<7, preferably less than 3), most preferably of 0.01 Nhydrochloric acid (HCl). The aqueous phase is kept at a temperaturebetween about 0 and about 60° C., preferably between about 0 and 20° C.,more preferred between about 5 and about 15° C., most preferably about5° C. The aqueous phase circulates out of the bottom valve of itsreservoir ((1) of FIG. 5) due to the stream created by the high shearmixer or with an auxiliary pump, preferably a rotary lobe pump, thenpasses through the high shear mixer, back into the reservoir.Preferably, the outlet of the loop is placed under the fluid levelmaintained in the reservoir, in order to prevent foaming.

The addition of the organic phase to the mixing chamber as mentioned instep (b) above is achieved via an injector nozzle which directly pointsinto the aqueous phase. Any conventional nozzle known to the person ofskill in the art can be used. Preferred injector nozzles show central oracentric geometry and have a diameter of about 1 to 10 mm. The acentric(not centered) geometry and a diameter of 5 mm are especially preferred.The injector nozzle may point to the rotor of the high shear mixing unitat an angle between 0 and 90°, preferably between 40 and 50°, mostpreferably at 45° (α, FIG. 6). During the process according to thepresent invention, the distance between the point of the injector nozzleand the tip of the rotor of the high shear mixing unit is about 1 to 10mm, preferably about 2 to 4 mm and most preferably about 2.6 mm. Theaddition of the organic phase is preferably carried out at dosing ratesof about 60/1 to about 300/1 (ratio of aqueous phase/organic phaseduring precipitation), preferably about 70/1 to about 120/1 and mostpreferably at about 100/1. Final ratio of aqueous phase/organic phaseafter precipitation is in the range of about 5/1-12/1 preferably7/1-10/1 and most preferably at 8.5/1.

While the organic phase is added (injected) into the aqueous phase ofthe mixing chamber, the high shear mixing unit is operating. Anyconventional high shear mixing unit (rotor/stator unit) known to theperson of skill in the art can be applied. The preferred rotor geometryaccording to the present invention uses a rotor/stator unit with aradial single teeth row or double teeth row or combination thereof. Thetip speed of the rotor is about 15 to about 25 m/sec., preferably 25m/sec.

Subsequent to the complete addition of the organic phase into theaqueous phase, the obtained suspension, thus the precipitate consistingof amorphous Compound I and HPMCAS in the aqueous phase, is furthercirculated in the closed loop containing the high shear mixing unit.Outside of the high shear mixing unit the circulation must be carriedout with the aid of an auxiliary pump, preferably a rotary lobe pump.The suspension is passed through the high shear mixing unit severaltimes, up to the moment where a desired particle size and/or particlesize distribution is obtained. Usually the suspension is passed throughthe high shear mixing unit about 1 to 60 times, most preferably 6 times.The particle size and/or particle size distribution can be determined bystandard techniques, well known to the person of skill in the art, suchas for example dynamic light scattering. The preferred particle sizeaccording to the present invention is with in the range of D50=80-230 μmpreferably D50=80-160 μm.

Isolation of the solid dispersion (MBP) according to step (e) above canbe carried out by using conventional filter techniques or centrifuges.Prior to isolation, the suspension is preferably adjusted to about 5 to10° C. Subsequently, the isolated solid dispersion is washed with acidicwater; preferably 0.01 N HCl followed by further washing with pure waterin order to substantially remove the organic solvent (step (f)). Theisolated (wet) solid dispersion (MBP) usually shows a water contentbetween 60 and 70% (w/w), which is preferably dried before any furtherprocessing. The drying can be carried out using any standard techniquesknown to the person of skill in the art, for example using a cabinetdryer at temperatures between 30 and 50° C., preferably at about 40° C.and at reduced pressure, preferably below 20 mbar. Several dryingprocedures can be combined or used sequentially, whereby the use offluidized bed drying is especially preferred as the final drying stepaccording to the present invention.

A specific method of making the (HPMCAS-Compound I) MBP according tosteps a) to g) above is described in Example 22, which forms a furtherpreferred embodiment of the present invention. The stability of thesolid dispersion (MBP) as obtained by the method of Example 22 wascompared with the stability of an MBP obtained via conventional sprayprecipitation. “Conventional spray precipitation” means that the organicphase was sprayed onto the aqueous phase via a nozzle which is placedoutside the aqueous phase, above its surface like is the case for manyconventional spray-precipitation techniques. All further processparameters are the same for both methods. The stability, thus theinhibition of re-crystallization of Compound I, is determined by x-raydiffraction measurements, using a conventional wide angle X-rayscattering setup as it is well known to the skilled artisan. Samplepreparation was identical for both MBP's. The samples were treated in aclimate chamber (50° C. and 90% humidity (RH)) for several hoursrespective days (0 h, 14 h, 41 h, 4 d, 6 d, 13 d) prior to X-raymeasurements. The results are shown in FIG. 7A for the MBP obtainedaccording to Example 22, and FIG. 7B for the MBP obtained by theconventional method. The earliest X-ray curves of both MBP's show abroad halo in the wide angle region with the absence of sharp signals,thereby evidencing that both materials are in an amorphous state. Withinseveral days, sharp signals occur in the X-ray curves obtained from theMBP manufactured by the conventional method (see FIG. 7B), but not inthe X-ray curves obtained from the MBP prepared using the methoddisclosed herein (see FIG. 7A).

In summary, the results presented in FIGS. 7A and 7B demonstrate thatthe spray precipitated MBP is less stable against re-crystallizationthan the high shear precipitated MBP as evidenced by the earlyoccurrence of sharp signals in the diffractograms (see FIG. 7B), whichcan be allocated to the crystalline form of Compound I. The bottom linein each figure represents the initial sample, the following lines bottomup after 14 h, 41 h, 96 h, 6 d respective 13 d storage in a climatecontrolled chamber (at 50° C. 90% RH).

The novel processes as provided herein can preferably be carried outusing a setup as shown in the accompanying FIG. 5.

A setup substantially as illustrated in FIG. 5 can be used for thefollowing preparation. Thus, FIG. 5 contemplates two reservoirs(vessels) with temperature control means, one for providing the aqueousphase at a controlled temperature (1), the other for providing theorganic phase at a controlled temperature (2). Both vessels are furtherequipped with automatic stirrers (3). The aqueous phase is circulated ina closed loop (4) using a pump (5), while passing through a high shearmixing unit (6). The organic phase is added into the aqueous phasewithin the high shear mixing unit with the aid of a dosing pump (7) andvia an injector nozzle which is shown in more detail in FIG. 6.

As shown in FIG. 6, the nozzle (8) is placed within the aqueous phaseinside the high shear mixing unit. The nozzle can be oriented withindifferent angles (a) with respect to the rotor (9) of the high shearmixing unit, and within defined distances (d) of the rotor tip.

The solid dispersion, in particular the MBP obtainable according to themethods provided can be used in a wide variety of forms foradministration of drugs such as Compound I, including drugs that arepoorly water soluble, and in particular for oral dosage forms. Exemplarydosage forms include powders or granules that can be taken orally eitherdry or reconstituted by addition of water to form a paste, slurry,suspension or solution; tablets, capsules, or pills. Various additivescan be mixed, ground or granulated with the solid dispersion asdescribed herein to form a material suitable for the above dosage forms.Potentially beneficial additives may fall generally into the followingclasses: other matrix materials or diluents, surface active agents, drugcomplexing agents or solubilizers, fillers, disintegrants, binders,lubricants, and pH modifiers (e.g., acids, bases, or buffers). Examplesof other matrix materials, fillers, or diluents include lactose,mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, andstarch. Examples of surface active agents include sodium lauryl sulfateand polysorbate 80. Examples of drug complexing agents or solubilizersinclude the polyethylene glycols, caffeine, xanthene, gentisic acid andcylodextrins. Examples of disintegrants include sodium starch gycolate,sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, andcroscarmellose sodium. Examples of binders include methyl cellulose,microcrystalline cellulose, starch, and gums such as guar gum, andtragacanth. Examples of lubricants include magnesium stearate andcalcium stearate. Examples of pH modifiers include acids such as citricacid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinicacid, phosphoric acid, and the like; bases such as sodium acetate,potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate,sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like,and buffers generally comprising mixtures of acids and the salts of saidacids. At least one function of inclusion of such pH modifiers is tocontrol the dissolution rate of the drug, matrix polymer, or both,thereby controlling the local drug concentration during dissolution.

Additives may be incorporated into the solid amorphous dispersion duringor after its formation. In addition to the above additives orexcipients, use of any conventional materials and procedures forformulation and preparation of oral dosage forms using the compositionsdisclosed herein known by those skilled in the art are potentiallyuseful.

Consequently, a further embodiment includes a pharmaceutical preparationcontaining the solid dispersion as obtained by a method as describedherein, in particular as obtained according to steps a) to g) asmentioned above, and more particularly as obtained according to theprocess described in Example 22.

In still another embodiment, there is provided a solid dispersion asobtained according to the present process for use as a medicament, inparticular a solid dispersion comprising HPMCAS and Compound I, moreparticularly the solid dispersion as obtained according the steps a) tog) above or according to Example 22.

In yet another embodiment there is provided the use of the soliddispersion obtainable by the present steps a) to g) or by the method ofExample 22 in the manufacture of medicaments for the treatment ofcancer, in particular solid tumors, and more particularly malignant(metastatic) melanomas.

In still another embodiment, there is provided the solid dispersion asobtained according to steps a) to g) above or the method of Example 22for use as a medicament for the treatment of cancer, in particular solidtumors, and more particularly malignant (metastatic) melanoma.

c) pH-Controlled Precipitation

The process involves the microprecipitation of Compound I in an ionicpolymer (for example, HPMC-AS). In this process, Compound I and thepolymer are dissolved at a high pH and precipitated by lowering the pHof the solution or vice versa.

In a preferred embodiment, the polymer is HPMC-AS which is insoluble atlow pH. Compound I and HPMC-AS are dissolved in an organic solvent suchas dimethylformamide, dimethylacetamide (DMA), dimethyl sulfoxide(DMSO), N-methylpyrrolidone (NMP), and the like. The pH of the solutionis then lowered, for example by adding an acid. Addition of the acidincludes mixing of the Compound I and polymer solution and the acid, forexample by adding acid to the Compound I and polymer solution, addingthe Compound I and polymer solution to the acid, or mixing the twosimultaneously. At the lowered pH, both Compound I and HPMC-ASsimultaneously precipitate out, resulting in a solid molecular complexcontaining Compound I embedded in a matrix formed by HPMC-AS. Theresulting solid molecular complex may then be washed with water toremove the organic solvent.

d) Hot Melt Extrusion Process

Microprecipitation of the Compound I in a polymer (such as HPMC-AS) canbe achieved in certain embodiments by a hot melt extrusion process.Compound I and the polymer are mixed and then fed continuously to atemperature-controlled extruder causing the Compound Ito be molecularlydispersed in the molten polymer. The resulting extrudate is cooled toroom temperature and milled into a fine powder.

e) Supercritical Fluid Process

In this process Compound I and a polymer (such as HPMC-AS) are dissolvedin a supercritical fluid such as liquid nitrogen or liquid carbondioxide. The supercritical fluid is then removed by evaporation leavingthe Compound I microprecipitated in the matrix formed by the polymer. Ina different method, the Compound I and a polymer (such as HPMC-AS) aredissolved in a suitable solvent. A microprecipitated powder can then beformed by spraying the solution in a supercritical fluid which acts asan antisolvent.

The resulting solid molecular complex prepared by any method may befurther processed to provide suitable bioavailability. The solidmolecular complex may be processed by roller compaction, for example thecomplex and other powders may be blended and roller compacted to form aribbon or sheet that is then milled, mixed with other excipients andencapsulated into 2-pc hard gelatin capsule shells at the desiredstrength.

Determination of Whether Compound I is in Amorphous Form

Whether Compound I has been successfully immobilized in amorphous formcan be determined by various means, including powder X-ray diffraction.In addition, the glass transition temperature of the complex can bemeasured using modulated DSC and this can also provide informationwhether the dispersion is a multiphase or uniphase. A uniphase isindicative of such immobilization.

Crystalline Polymorphs (A) Crystalline Polymorph Form 1

Crystalline polymorphs of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(Compound I) are provided. In one embodiment, crystalline polymorph Form1 is provided, wherein the polymorph exhibits a powder x-ray diffractionpattern having characteristic peak locations of approximately 4.7, 9.4,11.0, 12.5, and 15.4 degrees 2θ. In one embodiment, polymorph Form 1exhibits a powder x-ray diffraction pattern having characteristic peaklocations of approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 18.6,and 22.2 degrees 2θ. In one embodiment, polymorph Form 1 exhibits apowder x-ray diffraction pattern having characteristic peak locations ofapproximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 16.1, 18.6, 19.0,22.2 and 26.8 degrees 2θ. In one embodiment, crystalline polymorph Form1 exhibits a powder x-ray diffraction pattern substantially the same asthe powder x-ray diffraction pattern of FIG. 1. In one embodiment, apurified crystalline polymorph Form 1 is provided. In one embodiment, apurified crystalline polymorph Form 1 is used in the preparation of amesylate or tosylate salt form of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide.In one embodiment, a pharmaceutical composition comprising crystallinepolymorph Form 1 and at least one excipient or carrier is provided.

Methods of making crystalline polymorph Form 1 of propane-1-sulfonicacid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideare provided. The method may include recrystallization of any form ofpropane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidefrom a mixture of a lower ketone and a lower alcohol, e.g.,acetone:absolute ethanol. The propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidemay be recrystallized from acetone:absolute ethanol in a ratio of from1:1 to 5:1, preferably 2:1 by volume.

(B) Crystalline Polymorph Form 2

Crystalline polymorph Form 2 of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideis provided, wherein the polymorph exhibits a powder x-ray diffractionpattern having characteristic peak locations of approximately 8.8, 9.2,13.5, 19.1 and 24.4 degrees 2θ. In one embodiment, polymorph Form 2exhibits a powder x-ray diffraction pattern having characteristic peaklocations of approximately 6.7, 8.8, 9.2, 13.5, 15.0, 17.7, 19.1, 19.7,21.4 and 24.4 degrees 2θ. In one embodiment, polymorph Form 2 exhibits apowder x-ray diffraction pattern having characteristic peak locations ofapproximately 6.7, 8.8, 9.2, 13.5, 14.1, 14.5, 15.0, 16.2, 17.0, 17.7,19.1, 19.7, 21.4, 22.2, 24.1, 24.4, and 28.1 degrees 2θ. In oneembodiment, crystalline polymorph Form 2 exhibits a powder x-raydiffraction pattern substantially the same as the powder x-raydiffraction pattern of FIG. 2. In one embodiment, a purified crystallinepolymorph Form 2 is provided. In one embodiment, a purified crystallinepolymorph Form 2 is used in the preparation of a mesylate or tosylatesalt form of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide.In one embodiment, a pharmaceutical composition comprising crystallinepolymorph Form 2 and at least one excipient or carrier is provided.

Methods of making crystalline polymorph Form 2 of propane-1-sulfonicacid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideare provided, wherein the method comprises direct crystallization fromdimethylacetamide/methanol and recrystallization of any form ofpropane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidefrom a suitable ether (including cyclic ethers), ester or ketone solventsuch as methyl-t-butyl ether:tetrahydrofuran, ethyl acetate, or acetone.In one embodiment, Form 2 of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideis prepared by heating/melting any form of the compound andre-solidifying.

Mesylate Salt of Compound I

A mesylate salt form of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideis provided. In one embodiment, a mesylate salt form ofpropane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideis provided. In one embodiment, the mesylate salt form is substantiallycrystalline. In one embodiment, the mesylate salt form is partiallyamorphous. In one embodiment, the mesylate salt form is substantiallyamorphous. In one embodiment, the mesylate salt is used in amicroprecipitated bulk process to formulate the salt in an amorphousform. In one embodiment, the mesylate salt is generated in situ in amicroprecipitated bulk process to formulate the salt in an amorphousform. In one embodiment, a composition is provided comprising themesylate salt.

Tosylate Salt of Compound I

A tosylate salt of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideis provided. In one embodiment, the tosylate salt form is substantiallycrystalline. In one embodiment, the tosylate salt form is partiallyamorphous. In one embodiment, the tosylate salt form is substantiallyamorphous. In one embodiment, the tosylate salt is used in amicroprecipitated bulk process to formulate the salt in an amorphousform. In one embodiment, the tosylate salt is generated in situ in amicroprecipitated bulk process to formulate the salt in an amorphousform. In one embodiment, a composition is provided comprising thetosylate salt.

Kinase Targets and Indications

Protein kinases play key roles in propagating biochemical signals indiverse biological pathways. More than 500 kinases have been described,and specific kinases have been implicated in a wide range of diseases orconditions (i.e., indications), including for example withoutlimitation, cancer, cardiovascular disease, inflammatory disease,neurological disease, and other diseases. As such, kinases representimportant control points for small molecule therapeutic intervention.Description of specific target protein kinases contemplated by thepresent invention follow:

A-Raf: Target kinase A-Raf (i.e., v-raf murine sarcoma 3611 viraloncogene homolog 1) is a 67.6 kDa serine/threonine kinase encoded bychromosome Xp11.4-p11.2 (symbol: ARAF). The mature protein comprises RBD(i.e., Ras binding domain) and phorbol-ester/DAG-type zinc finger domainand is involved in the transduction of mitogenic signals from the cellmembrane to the nucleus. A-Raf inhibitors may be useful in treatingneurologic diseases such as multi-infarct dementia, head injury, spinalcord injury, Alzheimer's disease (AD), Parkinson's disease; neoplasticdiseases including, but not limited to, melanoma, glioma, sarcoma,carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal,ovarian), lymphoma (e.g. histiocytic lymphoma), neurofibromatosis,myelodysplastic syndrome, leukemia, tumor angiogenesis; pain ofneuropathic or inflammatory origin, including acute pain, chronic pain,cancer-related pain and migraine; and diseases associated with muscleregeneration or degeneration, including, but not limited to, vascularrestenosis, sarcopenia, muscular dystrophies (including, but not limitedto, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies),motor neuron diseases (including, but not limited to, amyotrophiclateral sclerosis, infantile progressive spinal muscular atrophy,intermediate spinal muscular atrophy, juvenile spinal muscular atrophy,spinal bulbar muscular atrophy, and adult spinal muscular atrophy),inflammatory myopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

B-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogenehomolog B1) is a 84.4 kDa serine/threonine kinase encoded by chromosome7q34 (symbol: BRAF). The mature protein comprises RBD (i.e., Ras bindingdomain), C1 (i.e., protein kinase C conserved region 1) and STK (i.e.,serine/threonine kinase) domains.

Target kinase B-Raf is involved in the transduction of mitogenic signalsfrom the cell membrane to the nucleus and may play a role in thepostsynaptic responses of hippocampal neurons. As such, genes of the RAFfamily encode kinases that are regulated by Ras and mediate cellularresponses to growth signals. Indeed, B-Raf kinase is a key component ofthe RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which plays afundamental role in the regulation of cell growth, division andproliferation, and, when constitutively activated, causes tumorigenesis.Among several isoforms of Raf kinase, the B-type, or B-Raf, is thestrongest activator of the downstream MAP kinase signaling.

The BRAF gene is frequently mutated in a variety of human tumors,especially in malignant melanoma and colon carcinoma. The most commonreported mutation was a missense thymine (T) to adenine (A) transversionat nucleotide 1796 (T1796A; amino acid change in the B-Raf protein isVal<600> to Glu<600>) observed in 80% of malignant melanoma tumors.Functional analysis reveals that this transversion is the only detectedmutation that causes constitutive activation of B-Raf kinase activity,independent of RAS activation, by converting B-Raf into a dominanttransforming protein. Based on precedents, human tumors developresistance to kinase inhibitors by mutating a specific amino acid in thecatalytic domain as the “gatekeeper”. (Balak, et. al., Clin Cancer Res.2006, 12:6494-501). Mutation of Thr-529 in BRAF to De is thusanticipated as a mechanism of resistance to BRAF inhibitors, and thiscan be envisioned as a transition in codon 529 from ACC to ATC.

Niihori et al., report that in 43 individuals withcardio-facio-cutaneous (CFC) syndrome, they identified two heterozygousKRAS mutations in three individuals and eight BRAF mutations in 16individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway isa common molecular basis for the three related disorders (Niihori etal., Nat. Genet. 2006, 38(3):294-6).

c-Raf-1: Target kinase c-Raf-1 (i.e., v-raf murine sarcoma viraloncogene homolog 1) is a 73.0 kDa STK encoded by chromosome 3p25(symbol: RAF1). c-Raf-1 can be targeted to the mitochondria by BCL2(i.e., oncogene B-cell leukemia 2) which is a regulator of apoptoticcell death. Active c-Raf-1 improves BCL2-mediated resistance toapoptosis, and c-Raf-1 phosphorylates BAD (i.e., BCL2-binding protein).c-Raf-1 is implicated in carcinomas, including colorectal, ovarian, lungand renal cell carcinoma. C-Raf-1 is also implicated as an importantmediator of tumor angiogenesis (Hood, J. D. et al., 2002, Science 296,2404). C-Raf-1 inhibitors may also be useful for the treatment of acutemyeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des2002, 8(25):2243-8). Raf-1 activators may be useful as treatment forneuroendocrine tumors, such as medullary thyroid cancer, carcinoid,small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al.,Anticancer Drugs 2006, 17(2):139-42).

A-Raf, B-Raf and/or C-Raf inhibitors may be useful in treatingA-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or conditionselected from the group consisting of neurologic diseases, including,but not limited to, multi-infarct dementia, head injury, spinal cordinjury, Alzheimer's disease (AD), Parkinson's disease, seizures andepilepsy; neoplastic diseases including, but not limited to, melanoma,glioma, sarcoma, carcinoma (e.g. gastrointestinal, liver, bile duct(cholangiocarcinoma), colorectal, lung, breast, pancreatic, thyroid,renal, ovarian, prostate), lymphoma (e.g. histiocytic lymphoma)neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome,leukemia, tumor angiogenesis, neuroendocrine tumors such as medullarythyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, andpheochromocytoma; pain of neuropathic or inflammatory origin, including,but not limited to, acute pain, chronic pain, cancer-related pain, andmigraine; cardiovascular diseases including, but not limited to, heartfailure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.thrombotic microangiopathy syndromes), atherosclerosis, and reperfusioninjury; inflammation and/or proliferation including, but not limited to,psoriasis, eczema, arthritis and autoimmune diseases and conditions,osteoarthritis, endometriosis, scarring, vascular restenosis, fibroticdisorders, rheumatoid arthritis, inflammatory bowel disease (IBD);immunodeficiency diseases, including, but not limited to, organtransplant rejection, graft versus host disease, and Kaposi's sarcomaassociated with HIV; renal cystic, or prostatic diseases, including, butnot limited to, diabetic nephropathy, polycystic kidney disease,nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycysticliver disease, tuberous sclerosis, Von Hippel Lindau disease, medullarycystic kidney disease, nephronophthisis, and cystic fibrosis; metabolicdisorders, including, but not limited to, obesity; infection, including,but not limited to Helicobacter pylori, Hepatitis and Influenza viruses,fever, HIV and sepsis; pulmonary diseases including, but not limited to,chronic obstructive pulmonary disease (COPD) and acute respiratorydistress syndrome (ARDS); genetic developmental diseases, including, butnot limited to Noonan's syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome,cardio-facio-cutaneous syndrome (CFC), and neural crest syndromeabnormalities causing cardiovascular, skeletal, intestinal, skin, hairand endocrine diseases; and diseases associated with muscle regenerationor degeneration, including, but not limited to, sarcopenia, musculardystrophies (including, but not limited to, Duchenne, Becker,Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic,Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motorneuron diseases (including, but not limited to, amyotrophic lateralsclerosis, infantile progressive spinal muscular atrophy, intermediatespinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbarmuscular atrophy, and adult spinal muscular atrophy), inflammatorymyopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

Alternative Compound Forms or Derivatives

Propane-1-sulfonic acid{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-2,4-difluoro-phenyl]-amide}contemplated herein is described with reference to the specificcompound. In addition, Compound I may exist in a number of differentforms or derivatives, all within the scope of the present inventions.Alternative forms or derivatives, include, for example, (a) prodrugs,and active metabolites (b) tautomers (c) pharmaceutically acceptablesalts and (d) solid forms, including different crystal forms,polymorphic or amorphous solids, including hydrates and solvatesthereof, and other forms.

Prodrugs and Metabolites

Prodrugs are compounds or pharmaceutically acceptable salts thereofwhich, when metabolized under physiological conditions or when convertedby solvolysis, yield the desired active compound. Prodrugs include,without limitation, esters, amides, carbamates, carbonates, ureides,solvates, or hydrates of the active compound. Typically, the prodrug isinactive, or less active than the active compound, but may provide oneor more advantageous handling, administration, and/or metabolicproperties. Prodrugs may include variants wherein an —NH group of thecompound has undergone acylation, such as the 1-position of thepyrrolo[2,3-b]pyridine ring or the nitrogen of the sulfonamide group ofCompound I or a pharmaceutically acceptable salt thereof, where cleavageof the acyl group provides the free —NH group of the active drug. Someprodrugs are activated enzymatically to yield the active compound, or acompound may undergo further chemical reaction to yield the activecompound. Prodrugs may proceed from prodrug form to active form in asingle step or may have one or more intermediate forms which maythemselves have activity or may be inactive.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can beconceptually divided into two non-exclusive categories, bioprecursorprodrugs and carrier prodrugs. Generally, bioprecursor prodrugs arecompounds that are inactive or have low activity compared to thecorresponding active drug compound, that contain one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollowing types:

Oxidative reactions: Oxidative reactions are exemplified withoutlimitation by reactions such as oxidation of alcohol, carbonyl, and acidfunctionalities, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative O— and 5-dealkylation, oxidative deamination,as well as other oxidative reactions.

Reductive reactions: Reductive reactions are exemplified withoutlimitation by reactions such as reduction of carbonyl functionalities,reduction of alcohol functionalities and carbon-carbon double bonds,reduction of nitrogen-containing functional groups, and other reductionreactions.

Reactions without change in the oxidation state: Reactions withoutchange in the state of oxidation are exemplified without limitation toreactions such as hydrolysis of esters and ethers, hydrolytic cleavageof carbon-nitrogen single bonds, hydrolytic cleavage of non-aromaticheterocycles, hydration and dehydration at multiple bonds, new atomiclinkages resulting from dehydration reactions, hydrolyticdehalogenation, removal of hydrogen halide molecule, and other suchreactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improves uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, the prodrug and anyrelease transport moiety are acceptably non-toxic. For prodrugs wherethe transport moiety is intended to enhance uptake, typically therelease of the transport moiety should be rapid. In other cases, it isdesirable to utilize a moiety that provides slow release, e.g., certainpolymers or other moieties, such as cyclodextrins. (See, e.g., Cheng etal., U.S. Patent Publ. No. 20040077595, application Ser. No. 10/656,838,incorporated herein by reference.) Such carrier prodrugs are oftenadvantageous for orally administered drugs. In some instances, thetransport moiety provides targeted delivery of the drug, for example thedrug may be conjugated to an antibody or antibody fragment. Carrierprodrugs can, for example, be used to improve one or more of thefollowing properties: increased lipophilicity, increased duration ofpharmacological effects, increased site-specificity, decreased toxicityand adverse reactions, and/or improvement in drug formulation (e.g.,stability, water solubility, suppression of an undesirable organolepticor physiochemical property). For example, lipophilicity can be increasedby esterification of hydroxyl groups with lipophilic carboxylic acids,or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols.Wermuth, supra.

Metabolites, e.g., active metabolites, overlap with prodrugs asdescribed above, e.g., bioprecursor prodrugs. Thus, such metabolites arepharmacologically active compounds or compounds that further metabolizeto pharmacologically active compounds that are derivatives resultingfrom metabolic processes in the body of a subject. Of these, activemetabolites are such pharmacologically active derivative compounds. Forprodrugs, the prodrug compound is generally inactive or of loweractivity than the metabolic product. For active metabolites, the parentcompound may be either an active compound or may be an inactive prodrug.For example, in some compounds, one or more alkoxy groups can bemetabolized to hydroxyl groups while retaining pharmacologic activityand/or carboxyl groups can be esterified, e.g., glucuronidation. In somecases, there can be more than one metabolite, where an intermediatemetabolite(s) is further metabolized to provide an active metabolite.For example, in some cases a derivative compound resulting frommetabolic glucuronidation may be inactive or of low activity, and can befurther metabolized to provide an active metabolite.

Metabolites of a compound may be identified using routine techniquesknown in the art, and their activities determined using tests such asthose described herein. See, e.g., Bertolini et al., 1997, J. Med.Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757;Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.

Tautomers

It is understood that some compounds may exhibit tautomerism. In suchcases, the formulae provided herein expressly depict only one of thepossible tautomeric forms. It is therefore to be understood thatCompound I provided herein is intended to represent any tautomeric formof the depicted compound and is not to be limited merely to the specifictautomeric form depicted by the drawing of the compound.

Pharmaceutically Acceptable Salts

Unless specified to the contrary, specification of Compound I hereinincludes pharmaceutically acceptable salts of such compound. Thus,Compound I can be in the form of pharmaceutically acceptable salts, orcan be formulated as pharmaceutically acceptable salts. Contemplatedpharmaceutically acceptable salt forms include, without limitation,mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable saltsare non-toxic in the amounts and concentrations at which they areadministered. The preparation of such salts can facilitate thepharmacological use by altering the physical characteristics of acompound without preventing it from exerting its physiological effect.Useful alterations in physical properties include lowering the meltingpoint to facilitate transmucosal administration and increasing thesolubility to facilitate administering higher concentrations of thedrug. Compound I possesses a sufficiently acidic and a sufficientlybasic functional group, and accordingly can react with any of a numberof inorganic or organic bases, and inorganic and organic acids, to forma pharmaceutically acceptable salt.

Pharmaceutically acceptable salts include acid addition salts such asthose containing chloride, bromide, iodide, hydrochloride, acetate,dichloroacetate, phenylacetate, acrylate, ascorbate, aspartate,benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, methylbenzoate, bicarbonate,butyne-1,4 dioate, hexyne-1,6-dioate, caproate, caprylate,chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate,glycolate, gluconate, glucarate, glucuronate, glucose-6-phosphate,glutamate, heptanoate, hexanoate, isethionate, isobutyrate,gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, maleate,hydroxymaleate, methylmaleate, malonate, mandelate, nicotinate, nitrate,isonicotinate, octanoate, oleate, oxalate, pamoate, phosphate,monohydrogenphosphate, dihydrogenphosphate, orthophosphate,metaphosphate, pyrophosphate, 2-phosphoglycerate, 3-phosphoglycerate,phthalate, propionate, phenylpropionate, propiolate, pyruvate, quinate,salicylate, 4-aminosalicylate, sebacate, stearate, suberate, succinate,sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, sulfamate,sulfonate, benzenesulfonate (i.e. besylate), ethanesulfonate (i.e.esylate), ethane-1,2-disulfonate, 2-hydroxyethanesulfonate (i.e.isethionate), methanesulfonate (i.e. mesylate), naphthalene-1-sulfonate,naphthalene-2-sulfonate (i.e. napsylate), propanesulfonate,p-toluenesulfonate (i.e. tosylate), xylenesulfonates,cyclohexylsulfamate, tartrate, and trifluoroacetate. Thesepharmaceutically acceptable acid addition salts can be prepared usingthe appropriate corresponding acid.

When acidic functional groups, such as carboxylic acid or phenol arepresent, pharmaceutically acceptable salts also include basic additionsalts such as those containing benzathine, chloroprocaine, choline,ethanolamine, diethanolamine, triethanolamine, t-butylamine,dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine,meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine,procaine, aluminum, calcium, copper, iron, lithium, magnesium,manganese, potassium, sodium, zinc, ammonium, and mono-, di-, ortri-alkylamines (e.g. diethylamine), or salts derived from amino acidssuch as L-histidine, L-glycine, L-lysine, and L-arginine. For example,see Remington's Pharmaceutical Sciences, 19^(th) ed., Mack PublishingCo., Easton, Pa., Vol. 2, p. 1457, 1995. These pharmaceuticallyacceptable base addition salts can be prepared using the appropriatecorresponding base.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent. If the particularcompound is an acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an appropriate inorganic or organic base.

Other Compound Forms

In the case of agents that are solids, it is understood by those skilledin the art that the compounds and salts may exist in different crystalor polymorphic forms, or may be formulated as co-crystals, or may be inan amorphous form, or may be any combination thereof (e.g. partiallycrystalline, partially amorphous, or mixtures of polymorphs) all ofwhich are intended to be within the scope of the present invention andspecified formulae. Whereas salts are formed by acid/base addition, i.e.a free base or free acid of the compound of interest forms an acid/basereaction with a corresponding addition base or addition acid,respectively, resulting in an ionic charge interaction, co-crystals area new chemical species that is formed between neutral compounds,resulting in the compound and an additional molecular species in thesame crystal structure.

In some instances, Compound I is complexed with an acid or a base,including base addition salts such as ammonium, diethylamine,ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine,meglumine; acid addition salts, such as acetate, acetylsalicylate,besylate, camsylate, citrate, formate, fumarate, glutarate,hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate,succinate, sulfate, tartrate, thiocyanate and tosylate; and amino acidssuch as alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine or valine. In combining Compound I with the acid orbase, an amorphous complex is preferably formed rather than acrystalline material such as a typical salt or co-crystal. In someinstances, the amorphous form of the complex is facilitated byadditional processing, such as by spray-drying, mechanochemical methodssuch as roller compaction, or microwave irradiation of the parentcompound mixed with the acid or base. Such amorphous complexes provideseveral advantages. For example, lowering of the melting temperaturerelative to the free base facilitates additional processing, such as hotmelt extrusion, to further improve the biopharmaceutical properties ofthe compound. Also, the amorphous complex is readily friable, whichprovides improved compression for loading of the solid into capsule ortablet form.

Additionally, Compound I or salts thereof described herein are intendedto cover hydrated or solvated as well as unhydrated or unsolvated formsof the identified material. For example, Compound I or salts thereofincludes both hydrated and non-hydrated forms. Other examples ofsolvates include the structures in combination with a suitable solvent,such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, aceticacid, or ethanolamine.

Formulations and Administration

Compound I or any form thereof as described herein (including solidmolecular complexes) will typically be used in therapy for humansubjects. However, Compound I and compositions thereof may also be usedto treat similar or identical indications in other animal subjects, andcan be administered by different routes, including injection (i.e.parenteral, including intravenous, intraperitoneal, subcutaneous, andintramuscular), oral, transdermal, transmucosal, rectal, or inhalant.Such dosage forms should allow the compound to reach target cells. Otherfactors are well known in the art, and include considerations such astoxicity and dosage forms that retard the compound or composition fromexerting its effects. Techniques and formulations generally may be foundin Remington: The Science and Practice of Pharmacy, 21^(st) edition,Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (herebyincorporated by reference herein).

In some embodiments, compositions (including solid complexes asdisclosed herein) include pharmaceutically acceptable carriers orexcipients, such as fillers, binders, disintegrants, glidants,lubricants, complexing agents, solubilizers, and surfactants, which maybe chosen to facilitate administration of the compound by a particularroute. Examples of carriers include calcium carbonate, calciumphosphate, various sugars such as lactose, glucose, or sucrose, types ofstarch, cellulose derivatives, gelatin, lipids, liposomes,nanoparticles, and the like. Carriers also include physiologicallycompatible liquids as solvents or for suspensions, including, forexample, sterile solutions of water for injection (WFI), salinesolution, dextrose solution, Hank's solution, Ringer's solution,vegetable oils, mineral oils, animal oils, polyethylene glycols, liquidparaffin, and the like. Excipients may also include, for example,colloidal silicon dioxide, silica gel, talc, magnesium silicate, calciumsilicate, sodium aluminosilicate, magnesium trisilicate, powderedcellulose, macrocrystalline cellulose, carboxymethyl cellulose,cross-linked sodium carboxymethylcellulose, sodium benzoate, calciumcarbonate, magnesium carbonate, stearic acid, aluminum stearate, calciumstearate, magnesium stearate, zinc stearate, sodium stearyl fumarate,syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate,glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate,hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seedoil mineral oil, polyethylene glycol (e.g. PEG 4000-8000),polyoxyethylene glycol, poloxamers, povidone, crospovidone,croscarmellose sodium, alginic acid, casein, methacrylic aciddivinylbenzene copolymer, sodium docusate, cyclodextrins (e.g.2-hydroxypropyl-.delta.-cyclodextrin), polysorbates (e.g. polysorbate80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000succinate), magnesium lauryl sulfate, sodium lauryl sulfate,polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols,or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylenesorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters,sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fattyacid such as oleic, stearic or palmitic acid, mannitol, xylitol,sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried,sucrose, fructose, calcium phosphate, dibasic calcium phosphate,tribasic calcium phosphate, calcium sulfate, dextrates, dextran,dextrin, dextrose, cellulose acetate, maltodextrin, simethicone,polydextrosem, chitosan, gelatin, HPMC (hydroxypropylmethyl celluloses),HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, hypromellose, andthe like.

In an embodiment of the present invention, a formulation is providedwhich comprises the aforementioned solid complex suspended in an aqueousvehicle. The formulation may further comprise colloidal silicon dioxidewhich has been found to stabilize the suspension. The silicon dioxide ispreferably present in an amount of at least 0.5% by weight of theformulation. The aqueous vehicle preferably is about 2% by weighthydroxypropyl cellulose.

In some embodiments, oral administration may be used. Pharmaceuticalpreparations for oral use can be formulated into conventional oraldosage forms such as capsules, tablets, and liquid preparations such assyrups, elixirs, and concentrated drops. Compound I may be combined withsolid excipients, optionally grinding a resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain, for example, tablets, coated tablets, hardcapsules, soft capsules, solutions (e.g. aqueous, alcoholic, or oilysolutions) and the like. Suitable excipients are, in particular, fillerssuch as sugars, including lactose, glucose, sucrose, mannitol, orsorbitol; cellulose preparations, for example, corn starch, wheatstarch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose(CMC), and/or polyvinylpyrrolidone (PVP: povidone); oily excipients,including vegetable and animal oils, such as sunflower oil, olive oil,or codliver oil. The oral dosage formulations may also containdisintegrating agents, such as the cross-linked polyvinylpyrrolidone,agar, or alginic acid, or a salt thereof such as sodium alginate; alubricant, such as talc or magnesium stearate; a plasticizer, such asglycerol or sorbitol; a sweetening such as sucrose, fructose, lactose,or aspartame; a natural or artificial flavoring agent, such aspeppermint, oil of wintergreen, or cherry flavoring; or dye-stuffs orpigments, which may be used for identification or characterization ofdifferent doses or combinations. Also provided are dragee cores withsuitable coatings. For this purpose, concentrated sugar solutions may beused, which may optionally contain, for example, gum arabic, talc,poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/ortitanium dioxide, lacquer solutions, and suitable organic solvents orsolvent mixtures.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compound may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols.

In some embodiments, injection (parenteral administration) may be used,e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous.Compound I and compositions thereof for injection may be formulated insterile liquid solutions, preferably in physiologically compatiblebuffers or solutions, such as saline solution, Hank's solution, orRinger's solution. Dispersions may also be prepared in non-aqueoussolutions, such as glycerol, propylene glycol, ethanol, liquidpolyethylene glycols, triacetin, and vegetable oils. Solutions may alsocontain a preservative, such as methylparaben, propylparaben,chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Inaddition, Compound I or compositions thereof may be formulated in solidform, including, for example, lyophilized forms, and redissolved orsuspended prior to use.

In some embodiments, transmucosal, topical or transdermal administrationmay be used. In such formulations of Compound I, penetrants appropriateto the barrier to be permeated are used. Such penetrants are generallyknown in the art, and include, for example, for transmucosaladministration, bile salts and fusidic acid derivatives. In addition,detergents may be used to facilitate permeation. Transmucosaladministration, for example, may be through nasal sprays orsuppositories (rectal or vaginal). Compositions of Compound I fortopical administration may be formulated as oils, creams, lotions,ointments, and the like by choice of appropriate carriers known in theart. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). In someembodiments, carriers are selected such that the active ingredient issoluble. Emulsifiers, stabilizers, humectants and antioxidants may alsobe included as well as agents imparting color or fragrance, if desired.Creams for topical application are preferably formulated from a mixtureof mineral oil, self-emulsifying beeswax and water in which mixture theactive ingredient, dissolved in a small amount of solvent (e.g., anoil), is admixed. Additionally, administration by transdermal means maycomprise a transdermal patch or dressing such as a bandage impregnatedwith an active ingredient and optionally one or more carriers ordiluents known in the art. To be administered in the form of atransdermal delivery system, the dosage administration will becontinuous rather than intermittent throughout the dosage regimen.

In some embodiments, Compound I or compositions thereof are administeredas inhalants. Compound I or compositions thereof may be formulated asdry powder or a suitable solution, suspension, or aerosol. Powders andsolutions may be formulated with suitable additives known in the art.For example, powders may include a suitable powder base such as lactoseor starch, and solutions may comprise propylene glycol, sterile water,ethanol, sodium chloride and other additives, such as acid, alkali andbuffer salts. Such solutions or suspensions may be administered byinhaling via spray, pump, atomizer, or nebulizer, and the like.Compound. I or compositions thereof may also be used in combination withother inhaled therapies, for example corticosteroids such as fluticasoneproprionate, beclomethasone dipropionate, triamcinolone acetonide,budesonide, and mometasone furoate; beta agonists such as albuterol,salmeterol, and formoterol; anticholinergic agents such as ipratropriumbromide or tiotropium; vasodilators such as treprostinal and iloprost;enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies;an oligonucleotide, such as single or double stranded DNA or RNA, siRNA;antibiotics such as tobramycin; muscarinic receptor antagonists;leukotriene antagonists; cytokine antagonists; protease inhibitors;cromolyn sodium; nedocril sodium; and sodium cromoglycate.

The amounts of Compound I or compositions thereof to be administered canbe determined by standard procedures taking into account factors such asthe compound activity (in vitro, e.g. the compound IC₅₀ vs. target, orin vivo activity in animal efficacy models), pharmacokinetic results inanimal models (e.g. biological half-life or bioavailability), the age,size, and weight of the subject, and the disorder associated with thesubject. The importance of these and other factors are well known tothose of ordinary skill in the art. Generally, a dose will be in therange of about 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of thesubject being treated. Multiple doses may be used.

Compound I or compositions thereof may also be used in combination withother therapies for treating the same disease. Such combination useincludes administration of Compound I and one or more other therapeuticsat different times, or co-administration of Compound I and one or moreother therapies. In some embodiments, dosage may be modified forCompound I or other therapeutics used in combination, e.g., reduction inthe amount dosed relative to a compound or therapy used alone, bymethods well known to those of ordinary skill in the art.

It is understood that use in combination includes use with othertherapies, drugs, medical procedures etc., where the other therapy orprocedure may be administered at different times (e.g. within a shorttime, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within alonger time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) thanCompound I or compositions thereof, or at the same time as Compound I orcompositions thereof. Use in combination also includes use with atherapy or medical procedure that is administered once or infrequently,such as surgery, along with Compound I or compositions thereofadministered within a short time or longer time before or after theother therapy or procedure. In some embodiments, the present inventionprovides for delivery of Compound I or compositions thereof and one ormore other drug therapeutics delivered by a different route ofadministration or by the same route of administration. The use incombination for any route of administration includes delivery ofCompound I or compositions thereof and one or more other drugtherapeutics delivered by the same route of administration together inany formulation, including formulations where the two compounds arechemically linked in such a way that they maintain their therapeuticactivity when administered. In one aspect, the other drug therapy may beco-administered with Compound I or compositions thereof. Use incombination by co-administration includes administration ofco-formulations or formulations of chemically joined compounds, oradministration of two or more compounds in separate formulations withina short time of each other (e.g. within an hour, 2 hours, 3 hours, up to24 hours), administered by the same or different routes.Co-administration of separate formulations includes co-administration bydelivery via one device, for example the same inhalant device, the samesyringe, etc., or administration from separate devices within a shorttime of each other. Co-formulations of Compound I and one or moreadditional drug therapies delivered by the same route includespreparation of the materials together such that they can be administeredby one device, including the separate compounds combined in oneformulation, or compounds that are modified such that they arechemically joined, yet still maintain their biological activity. Suchchemically joined compounds may have a linkage that is substantiallymaintained in vivo, or the linkage may break down in vivo, separatingthe two active components.

EXAMPLES

Examples related to the present invention are described below. In mostcases, alternative techniques can be used. The examples are intended tobe illustrative and are not limiting or restrictive to the scope of theinvention.

Example 1

This example describes the formation of a solid molecular complexcomprising Compound I and HPMC-AS.

Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand HPMC-AS in a ratio of 3:7 (30% compound and 70% polymer) weredissolved in dimethylacetamide (DMA). The resulting solution was thenadded with stirring to very cold dilute hydrochloric acid resulting inthe co-precipitation of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand HPMC-AS as a solid molecular complex wherein propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidewas present in a nanoparticulate size range. The ratio of DMA to acidwas in the range of 1:5 to 1:10. The co-precipitate was then washed withwater to remove DMA, filtered, dried to <2% moisture content and passedthrough a #30 mesh screen prior to evaluation. The resulting solidmolecular complex was 30% by weight propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand 70% by weight HPMC-AS.

The properties of the resulting solid molecular complex were as follows.

Property Measure X-ray pattern Amorphous Tg (range C.) 100-120 Drugloading (% w/w)  30 Bulk Density (g./cm3) 0.15-0.45 Absolute Density(g/cm3)   1-1.5 Specific Surface Area (cm2/g)  3-10 Intrinsic particlesize (nm) 150 Moisture Content   <2% DMA Content <0.2%

Examples 2 to 7

Solid molecular complexes comprising Compound I and HPMC-AS wereprepared using methods analogous to that used in Example 1 to producesolid molecular complexes wherein the ratio of the amount by weight ofpropane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidewithin the solid molecular complex to the amount by weight of the ionicpolymer therein is 3:7, 5:5, 5:5, 4:6, 4:6, and 2:8, respectively.

The solid molecular complexes produced in Examples 1 to 7 were evaluatedfor amorphous nature by powder XRD. The samples were exposed under OPENconditions by placing the sample in a bottle in the stability chamberwithout a lid or closure or cap on the at 40° C. and 75% relativehumidity (RH) and the properties of the solid molecular complexesfollowing such exposure were observed. The exposure periods are shown inthe table below. At the end of the exposure period, a sample of thepowder was taken from the bottle and placed in powder X-ray diffraction(XRD) chamber and diffraction pattern obtained. The samples were deemedstable if the powder XRD profile did not show crystalline peaks. Theprepared and stored samples were also evaluated by polarized lightmicroscopy. The incidence of polarized light results in a birefringencephenomenon, if crystals are present in the sample. For an amorphoussample, such a test could indicate presence of crystal material whichindicates that amorphous material is unstable.

TABLE 1 Evaluation of drug-HPMC-AS solid molecular complexes at varyingratios Results after open Drug:Polymer Lot number exposure at Ex. ratioZG-37427-xxx 40° C./75% RH 1 3:7 −183 STABLE after storage for up to 3months 2 3:7 −194 STABLE after storage for up to 3 months 3 5:5 −175UNSTABLE due to very small crystal peaks after storage for 3 weeks 4 5:5−185 UNSTABLE due to crystal peaks after 2 months 5 4:6 −154 STABLEafter 3 weeks of storage No apparent birefringence by microscopy 6 4:6−178 STABLE after storage for up to 2 months 7 2:8 −199 STABLE afterstorage for 1 month

Example 8

This example describes the formation of a solid molecular complexcomprising propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand EUDRAGIT® L 100. Eudragit L 100 is another anionic polymer, apolymethyl methacrylate ester with methacrylic acid as a functionalgroup and dissolves at pH 6.0 and above.

Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand EUDRAGIT® L 100 in a ratio of 3:7 (30% compound and 70% polymer)were dissolved in dimethylacetamide (DMA). The resulting solution wasthen added with stirring to very cold dilute hydrochloric acid resultingin the co-precipitation of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand Eudragit L 100 as a solid molecular complex wherein the drug waspresent in a nanoparticulate size range. The co-precipitate was thenwashed with water to remove DMA, filtered, dried, and milled to a finepowder. The ratio of DMA to acid was in the range of 1:5 to 1:10. Theco-precipitate was then washed with water to remove DMA, filtered, driedto <2% moisture content and passed through a #30 mesh screen prior toevaluation. The resulting solid molecular complex was 30% by weightpropane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand 70% by weight Eudragit L 100.

The solid molecular complex samples were evaluated for amorphous natureright after preparation by powder XRD. The samples were the subjected tostorage under OPEN conditions at 40 C/75% RH for varying periods of timesimilar to that shown in Examples 1-7. At the end of the exposureperiod, a sample of the powder was taken from the bottle and placed inpowder X-ray diffraction (XRD) chamber and diffraction pattern obtained.The samples were deemed stable if the powder XRD profile did not showcrystalline peaks. The prepared and stored samples were also evaluatedby polarized light microscopy. The incidence of polarized light resultsin a birefringence phenomenon, if crystals are present in the sample.For an amorphous sample, such a test could indicate presence of crystalmaterial which indicates that amorphous material is unstable. Resultsfor this Example are shown in Table 2 below.

Example 9

This example was performed with all the same steps as Example 8, withthe exception that propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand EUDRAGIT® L 100 were dissolved in dimethylacetamide (DMA) in a ratioof 4:6 (40% compound and 60% polymer) instead of 3:7 as in Example 8.Results for this Example are shown in Table 2 below.

Example 10

Solid molecular complexes containing the propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand Eudragit L 100-55 in ratios of 4:6 and 5:5, respectively, wereformed using the microprecipitation process same as that in Example 1.Eudragit L 100-55 is similar to L 100 except that it dissolves at pH 5.5and above and therefore more closely resembles HPMC-AS in its pHsolubility profile. The prepared and stored samples were evaluated bypowder XRD. Results for this Example are shown in Table 2 below.

Example 11

This example describes the formation of a solid molecular complexcomprising the propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand hydroxypropylmethylcellulose phthalate (HPMCP), another anionicpolymer used for enteric purposes. HPMCP is a cellulose polymer in whichsome of the hydroxyl groups are replaced with phthalyl esters from27-35%. It starts dissolving at pH 5.5 and higher. Solid molecularcomplexes containing propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand HPMCP in 1:1 ratio were prepared using same process as that used inExample 1. The prepared and stored samples were evaluated by XRD.Results for this Example are shown in Table 2 below.

TABLE 2 Evaluation of drug-polymer solid molecular complexes at varyingratios Drug Storage under open Lot # Polymer conditions at Ex. PolymerZG-37427-xxx Ratio Initial 40 C./75% RH 8 Eudragit L100 −192 3:7Amorphous, STABLE for up to 3 STABLE months 9 Eudragit L 100 −155 4:6Amorphous, UNSTABLE; STABLE birefringence observed in polarized lightmicroscopy after 3 weeks 10 Eudragit L100-55 −170 5:5 Amorphous,UNSTABLE, crystal STABLE peaks seen after 3 weeks 11 HPMCP −187 5:5Crystalline, UNSTABLE

Based on Examples 1-11, the propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide-polymerratio of 4:6 was the highest drug loading (40%) sustainable upon storagewith HPMC-AS as polymer. Therefore, this ratio was chosen for comparisonwith other polymers in a separate study.

Examples 12-16 were prepared by a microprecipitation process similar tothat for Example 1. The dried powder samples were evaluated foramorphous nature right after preparation by powder XRD. The samples werefurther subjected to storage under OPEN conditions at 40 C/75% RH forvarying periods of time similar to that shown in Examples 1-7. Theresults are shown in Table 3 below.

Example 12

Solid molecular complexes containing propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand HPMC-AS in ratio of 4:6 were found to be amorphous right afterpreparation (Table 3) and subject to storage for 4 weeks at 40 C/75% RH.

The XRD of the solid molecular complexes were evaluated.

Example 13

Solid molecular complexes containing propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand HPMCP in ratio of 4:6 were found to be amorphous right afterpreparation (Table 3) and subject to storage for 4 weeks at 40 C/75% RH.

Example 14

Solid molecular complexes containing propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand Eudragit L 100-55 in 4:6 ratio was found to be amorphous right afterpreparation (Table 3) and subject to storage for 4 weeks at 40 C/75% RH.

Example 15

Solid molecular complexes containing propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand polyvinylacetate phthalate (PVAP) in 4:6 ratio was crystalline rightafter preparation and therefore not subject to further testing. PVAP isan anionic enteric polymer formed as the phthalate ester ofpolyvinylacetate and contains 55-62% of phthalyl groups. It has a low Tgof 42.5 C which renders it unsuitable as a stabilizing polymer matrix.It dissolves at pH>5.

Example 16

Solid molecular complexes containing propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand cellulose acetate phthalate (CAP) in ratio of 4:6 was crystallineright after preparation and therefore not subject to further testing.

The powder XRD profiles of Examples 12-16 at the initial stage rightafter preparation are shown in Table 3.

TABLE 3 Evaluation of drug-polymer solid molecular complexes at fixedratio of 4:6 (40% drug and 60% polymer): Lot # Ex. Polymer ZG-39422-xxxInitial XRD 12 HPMC-AS, LF −129A STABLE Amorphous 13 HPMCP −129B STABLEAmorphous 14 Eudragit L100-55 −129C STABLE Amorphous 15 PVAP −129DUNSTABLE Crystalline 16 CAP −129E UNSTABLE Crystalline

After 1 week, the sample prepared under Example 13 showed a small peakin powder XRD indicating conversion to crystalline form. This peakbecame more pronounced after 2 weeks of storage.

Example 17

Samples prepared in Examples 12 and 14 did not indicate any crystallinepeak in powder XRD profiles up to the end of 4 weeks of storage.

In order to further differentiate the samples from Examples 12 and 14,the samples were subject to dissolution test by placing an amount ofsolid molecular complex equivalent to 80 mg of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidein 900 mL of pH 6.8 phosphate buffer medium containing 0.09% HTABsurfactant in USP Paddle dissolution apparatus at a speed of 75 rpm.

In one set of experiments, a sieve cut of granules of Examples 12 and 14were obtained by separating the #25/40 mesh sieve size fraction andsubjecting to dissolution test. The HPMC-AS solid molecular complexeshad increased amounts with respect to % dissolved as compared toEudragit L 100-55 solid molecular complexes, with the HPMC-AS solidmolecular complexes being about 85% dissolved at 200 minutes and withthe Eudragit L 100-55 solid molecular complexes being about 40%dissolved at 200 minutes.

In another experiment, the solid molecular complex samples from Examples12 and 14 were pre-wetted with vehicle containing hydroxypropylcellulose (Klucel) for improved dispersion and subjected to dissolutiontest. The HPMC-AS solid molecular complexes had increased amounts withrespect to % dissolved as compared to Eudragit L 100-55 solid molecularcomplexes, with the HPMC-AS solid molecular complexes being about 60-65%dissolved at 200 minutes and with the Eudragit L 100-55 solid molecularcomplexes being about 20-25% dissolved at 200 minutes.

Based on results from these experiments, the HPMC-AS was a superiorpolymer in stabilizing the drug upon storage under stress conditions butalso enabling drug release and maintaining supersaturation of amorphousdrug during dissolution without reverting to crystalline form within theperiod of testing. The Eudragit L 100-55 did not enhance drug release ascompared to HPMC-AS and therefore is not expected to provide theexposure and bioavailability as well as HPMC-AS. At the end of 3 h,almost 90% drug was released from Example 12 (HPMC-AS) while Example 14(Eudragit L-100-55) had only about 50% drug released. Thus, apropane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideand HPMC-AS solid molecular complex made by the microprecipitationprocess therefore not only stabilizes the amorphous compound forhandling and storage but also ensures rapid drug release resulting insuperior dissolution and therefore bioavailability.

Example 18

This Example demonstrates the stabilization of solid molecular complexesin aqueous systems. The solid molecular complex of drug-HPMC-AS issuspended in an aqueous vehicle containing 2% hydroxypropylcellulose(Klucel LF). Upon addition of >0.5% w/w colloidal silicon dioxide, theresulting suspension was found to be stable for up to 8 h under normalconditions and for up to 24 h under refrigerated conditions.

Example 19

Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidecan exist in polymorphic forms, for example as polymorphic forms 1 or 2,where such polymorphic forms may be isolated as the substantially purepolymorph. The desired polymorphic form may be prepared, for example, byusing appropriate crystallization conditions. For example, Form 1 wasisolated by recrystallization from acetone/absolute ethanol (e.g. 1:1 to5:1, preferably 2:1 by volume) as explained in detail herein. Form 2 canbe formed for example directly via crystallization fromdimethylacetamide/methanol or under a variety of recrystallizationconditions, for example, is formed by recrystallization frommethyl-t-butyl ether/tetrahydrofuran, ethyl acetate, acetone, or isformed by heating/melting and re-solidifying any solid form, such aspolymorph Form 1, or a mixture of solid forms. The substantially pureisolated polymorphic forms were characterized by X-Ray PowderDiffraction (XRPD), differential scanning calorimetry (DSC) and infraredspectroscopy (See Example 20 below).

To demonstrate the formation of polymorphic Form 1, propane-1-sulfonicacid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(7.8 kg) was treated with acetone:absolute ethanol (1:4 by volume, 19kg) in a reactor and agitated at 20° C.±5° C. for at least 6 hours. Thecontents were filtered and the solids were washed with acetone:absoluteethanol (1:4 by volume) mixture. Solids were treated withtetrahydrofuran (26.6 kg), and the suspension was heated to 60° C.±5° C.for at least 30 minutes and agitated. The mixture was cooled to 55°C.±5° C. and methyl-t-butyl ether (92.3 kg) was added. The resultingsuspension was cooled to 20° C.±5° C. for at least 1 hour. The contentswere filtered and the solids were washed with methyl-t-butyl ether anddried. The solid was treated with acetone:absolute ethanol (2:1 byvolume) in a reactor. The contents were agitated and the suspension washeated at 60° C. until a solution was achieved. The solution wasfiltered through a large polish filter to remove any residual solid fromthe methyl-t-butyl ether treatment step. The filtrate was concentratedunder vacuum, stirred at 20° C.

+5° C. for at least 30 minutes and filtered. The solids were washed withpre-cooled (0° C. to −5° C.) ethanol and dried at 45° C. followed bydrying at 75° C. under vacuum until a constant weight was achieved, toprovide pure propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidepolymorphic Form 1. Form 1 was also prepared treating a sample with 120mL of acetone:ethanol (1:1 by volume) at refluxing, then filtering hotand removing solvent from the filtrate under vacuum until solidprecipitates out.

Example 20

The propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidepolymorphic Form 1 and Form 2 were characterized by X-ray powderdiffraction, infra-red spectrometry, and differential scanningcalorimetry. Samples were analyzed by X-ray powder diffraction (XRPD)using a ShimadzuXRD-6000 X-ray powder diffractometer using Cu Kαradiation. The tube voltage and amperage were set to 40 kV and 40 mA,respectively. The divergence and scattering slits were set at 1° and thereceiving slit was set at 0.15 mm. Diffracted radiation was detected bya NaI scintillation detector. A θ-2θ continuous scan at 3°/min (0.4sec/0.02° step) from 2.5° to 40° 2θ was used. A silicon standard wasanalyzed to check the instrument alignment. Data were collected andanalyzed using XRD-6100/7000 v.5.0. Sample was prepared for analysis byplacing it in an aluminum holder with silicon insert. The results areprovided in FIG. 1 (Form 1) and FIG. 2 (Form 2) and the following Table4.

TABLE 4 XRPD 2θ values for P-0001 polymorphic Form 1 and Form 2. 2θvalue (+/−0.2) Form 1 Form 2 4.7 6.7 8.8 9.4 9.2 10.0 11.0 12.5 13.514.2 14.1 14.5 14.9 15.0 15.4 16.1 16.2 17.0 17.3 17.7 18.6 18.3 19.019.1 19.7 20.6 20.0 20.9 21.2 21.4 21.6 22.0 22.2 22.2 23.2 23.9 23.824.1 24.4 25.1 25.7 6.1 26.6 6.8 28.1 28.8 9.2 29.3 30.1 31.1 31.7 34.534.9 35.9 39.2 41.3

The propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidepolymorphic Form 1 and Form 2 were further analyzed by infra-redspectrometry. Table 5 provides the characteristic wavenumbers observedfor each sample.

TABLE 5 IR absorption spectrum wavenumber values for P-0001 polymorphicForm 1 and Form 2. Wavenumber cm⁻¹ Form 1 Form 2 3238 3266 3121 29692879 2880 1709 1645 1639 1590 1589 1519 1519 1485 1487 1417 1417 13311322 1305 1306 1280 1287 1246 1246 1211 1215 1149 1143 1102 1096 10221027 1013 1012 965 968 915 916 891 893 857 825 825 796 798 773 767 717685 683 651 662 631 607 587 585 564 558 550 532 532 516 508 503

The propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidepolymorphic Form 1 and Form 2 were also analyzed by differentialscanning calorimetry (DSC), scanning at 10.00° C. per minute. The DSCthermogram for Form 1 shows an exothermic shift at approximately152-164° C. and an endothermic peak at 268.0° C. The DSC thermogram forForm 2 shows an endothermic peak at 271.2° C.

Example 21

Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideis characterized as having functionalities providing both weakly basicand weakly acidic centers which can form organic salt complexes,resulting in improved solubility. For example, the N-7 of the azaindoleportion is weakly basic (pKa approximately 4-5) and can form an acidaddition salt complex with an organic acid such as benzenesulfonic acid,methylsulfonic acid or toluenesulfonic acid, preferably methanesulfonicacid or toluenesulfonic acid. Such mesylate or tosylate salts provideadvantage over the free base, such as an improved solubility, improvedintrinsic dissolution rate, and lower melting point than the free base.The improved intrinsic dissolution rate provides an advantage informulation of the salt, for example, formulation in an amorphous formby methods described in the above examples. The improved solubilityprovides more efficient and cost effective formulation, for examplespray drying or microprecipitated bulk processing can be performed usingfar less solvent volumes due to the intrinsic solubility. Suchadvantages may also be provided by formation of the mesylate or tosylatesalt in situ during the processing, for example the process of spraydrying, solvent controlled precipitation, or pH controlledprecipitation. Also, lowered melting of the salt forms provides a moreefficient hot melt extrusion process, allowing for the melt to proceedat lower temperatures.

Acid addition salts, including sulfonic acid series of organic anionssuch as tosylate, besylate or mesylate, of Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideare preferably formed using acetone, which provides solubility of thefree base and is a non-solvent once the salt is formed. Typically,Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideis added to 20-50 solvent volumes of acetone with stirring and heating(30-35° C.), followed by the addition of 1 equivalent of the desiredacid counter ion. The solution is slowly cooled to 2-8° C. and the solidis isolated by either filtration or centrifugation, followed by vacuumdrying. The resulting solid may be amorphous, partially amorphous orcrystalline, and can be recrystallized as needed fromalcohol:acetone:ethyl acetate or alcohol alone to obtain the desiredsolid in crystalline form.

The mesylate salt of propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amidewas prepared by suspending 5 g (9.7 mmol) of polymorph Form 2 in 100 mLof acetone, mixing with heating 30-35° C. Methanesulfonic acid (0.63 mL,9.7 mmol) was added and the solution cooled to 5° C. over 30 minutes.The resulting solid was isolated by filtration, washed and dried undervacuum to provide the desired salt. The tosylate salt was preparedsimilarly. Exemplary XRPD patterns for the mesylate and tosylate saltsare provided in FIGS. 3 and 4, respectively, as compared to the freebase polymorph Form 2. The DSC thermogram for the mesylate salt shows anendothermic peak at approximately 231° C. The DSC thermogram for thetosylate salt shows an endothermic peak at approximately 223° C. andanother at approximately 253° C.

The resulting salts are processed through the techniques discussed inthe above examples, such as spray drying, solvent controlledprecipitation, pH controlled precipitation, or hot melt extrusion toprovide the preferred amorphous form, or further processed with suitableexcipient materials to provide for a directly compressible orencapsulated dosage form. The salt forms have advantages in suchprocesses, such as to minimize solvent utilization, increase yield,purity and throughput, as well as achieve constructs not attainableusing conventional solvent techniques.

Example 22

This example describes the preparation of a solid dispersion (MBP) ofamorphous Compound I in HPMCAS

Preparation of the DMA Phase:

The concentration of Compound I and HPMCAS in the organic solvent was35% (w/w), while the ratio of Compound I and HPMCAS is 30 to 70: Thetemperature of the solution was adjusted to 70° C.

In a 250 ml double jacketed glass flask reactor 21 g of Compound I weredissolved in 130 g Dimethylacetamide (DMA) at 20-25° C. Under stirring.48.9 g of HPMC-AS were added to the solution. The mixture was heated upto 70° C. A clear solution was obtained.

Preparation of the Aqueous Phase

In a double jacketed 2.0 liter reactor such as illustrated in FIG. 5,1210 g of 0.01 N HCl was tempered to 5° C. Out of the bottom valve ofthe reactor the water phase was circulated by the high shear mixer orwith an auxiliary pump, preferred a rotary lobe pump, and then followedby the high shear mixer, back to the top of the reactor. The inlet ofthe recirculation into the reactor was under the fluid level in order toprevent foaming (see FIG. 5).

Precipitation

High Shear Mixer (HSM)

The tip speed of the rotor in the high shear mixer was set 25 m/sec. Arotor/stator combination with one teeth row, each for rotor and statorwas used.

Dosing of the DMA solution

The DMA solution tempered at 70° C. was dosed with a gear pump via aninjector nozzle, which was pointing into the mixing chamber of the highshear mixer, into the circulating aqueous phase.

Dosing Rate of the DMA Solution

The DMA solution was dosed into the aqueous phase resulting in a ratioof HCl/DMA, in the mixing chamber of the high shear mixer of 100/1.

Additional Dispersing in the HSM (after Precipitation), Isolation andWashing

After addition of the DMA solution the obtained MBP suspension wasdispersed for an additional time, corresponding to equivalents of thebatch passing the high shear mixer. The time was corresponding to aturnover in calculated recirculation times of the batch of 6 times.

The obtained suspension, held at 5-10° C. was separated from the solidMBP. This was done by using a suction filter. The isolated MBP waswashed with 0.01 N HCl (15 kg 0.01 N HO/kg MBP) followed by washing withwater (5 kg water/kg MBP) in order to remove the DMA. The isolated (wet)MBP had a water content between 60 and 70%.

Delumping and Drying

Prior to drying the (wet) MBP was delumped by using a sieve mill. The(wet) MBP was dried in a cabinet dryer. During the drying process of theMBP the temperature of the product was below 40° C. in order to avoidrecrystallization of the API. The pressure inside the cabinet dryer wasbelow 20 mbar. The water content of the MBP after drying was below 2.0%and was signed amorphous in the XRPD pattern.

Example 23

This example describes the spray dry formation of a solid molecularcomplex comprising Compound I and HPMC-AS.

Compound I is prepared with a polymer such as HPMCAS, optionallyincluding a surfactant (e.g. an ionic surfactant such as sodium,1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (Docusate Sodium) ora nonionic surfactant such as Polysorbate 80). In general, a suitablesolvent system, such as 20:80 (w/w) tetrahydrofuran:acetone isequilibrated to 30° C., and Compound I is added to a level of 2-10%solids in 4-6 portions with stirring. HPMCAS at a suitable ratio, forexample 70:30 w/w HPMCAS:Compound I, is added (alternatively HPMCAS andsurfactant at for example 65:5:30 HPMCAS:surfactant:Compound I) isadded. The temperature is raised to 35-40° C., and the system optionallyfiltered to ensure removal of any unsolubilized solids. The solution isthen spray dried to provide spherical particles with a size distributionof 1-20 microns. Further processing may include drying of the materialin a fluid bed or tray dryer, and the resulting material may bedensified, for example, by roller compaction. As an example, Compound Iand HPMCAS in a ratio 30:70 (w/w) were dissolved to a level of 5.4%solids in a blend of 20:80 (w/w) tetrahydrofuran and acetone. Theresulting solution was then spray dried to produce a solid dispersion,amorphous powder. The solution was spray dried using a suitable spraydryer, e.g., a GEA-Niro SDMICRO™ Spray Dryer for smaller batches (e.g.10 gm solids) and a Niro Mobile Manor Spray Dryer for larger batches(e.g. 1 kg solids). For example, for a 10 μm batch, 35.0 gm oftetrahydrofuran was blended with 140.0 gm of acetone in a glass beaker,and 3.0 gm of Compound I was added with stirring for 10 minutes todissolve; 7.0 gm of HPMCAS-L (Shin-Etsu grade NF) was then added andstirred. While the solids appeared to be dissolved, the solution wasfiltered through filter paper prior to spray drying. The solution wasspray dried with the GEA-Niro SDMICRO™ Spray Dryer with inlet/outletconditions of 85° C. and 55° C., respectively, with atomization gaspressure at 0.5 bar. The spray dried material was collected in thecyclone collector, 5.78 gm or 58% yield.

A 1.6 kg batch was also prepared, where the solution was preparedsimilarly, only instead of filtering, the solution was stirred overnightat room temperature to ensure all solids were dissolved. A 200 meshscreen was attached to the end of the feed hose to remove anyun-dissolved particles and the solution was spray dried using the MobileManor Spray Dryer. The inlet/outlet conditions were 100° C. and 55° C.,respectively, with atomization gas pressure at 1.0 bar, with gas flowrate of 90 kg/hr. The material was spray dried over two days, andmaterial collected after the first day was subjected to vacuum drying at45° C. to remove residual solvents. The collected material was assessedfor bulk density (0.23 gm/mL), particle size (8 microns with a normaldistribution and standard deviation of 3 microns), residual solvent(after 89 hours of vacuum drying, the large batch had residual solventsof 0.001% acetone and 0.017% tetrahydrofuran), polarized lightmicroscopy, DSC (the DSC thermogram for the small batch shows anendothermic peak at approximately 243° C., while the thermogram for thelarge batch showed essentially no peak) and XRPD (which showed anamorphous material).

All patents and other references cited in the specification areindicative of the level of skill of those skilled in the art to whichthe invention pertains, and are incorporated by reference in theirentireties, including any tables and figures, to the same extent as ifeach reference had been incorporated by reference in its entiretyindividually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention. Forexample, variations can be made to crystallization or co-crystallizationconditions for Ret and Ret surrogate proteins and/or various kinasedomain sequences can be used. Thus, such additional embodiments arewithin the scope of the present invention and the following claims.

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. Thus, for an embodiment of the invention using one of the terms,the invention also includes another embodiment wherein one of theseterms is replaced with another of these terms. In each embodiment, theterms have their established meaning. Thus, for example, one embodimentmay encompass a method “comprising” a series of steps, anotherembodiment would encompass a method “consisting essentially” of the samesteps, and a third embodiment would encompass a method “consisting of”the same steps. The terms and expressions which have been employed areused as terms of description and not of limitation, and there is nointention that in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any 2 different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

Thus, additional embodiments are within the scope of the invention andwithin the following claims.

1. A solid dispersion comprising Compound I molecularly dispersed withina polymer matrix formed by an ionic polymer in its solid state.
 2. Asolid dispersion according to claim 1, wherein said ionic polymer isselected from the group consisting of hydroxypropylmethyl celluloseacetate succinate, hydroxypropylmethyl cellulose, hydroxypropyl methylcellulose phthalate and methacrylic acid copolymers.
 3. A soliddispersion according to claim 2, wherein said ionic polymer is selectedfrom the group consisting of hydroxypropylmethyl cellulose acetatesuccinate, hydroxypropylmethyl cellulose and methacrylic acidcopolymers.
 4. A solid dispersion according to claim 1, wherein saidpolymer is hydroxypropylmethyl cellulose acetate succinate (HPMCAS). 5.A solid dispersion according to claim 1, wherein said polymer comprisesa methacrylic acid copolymer.
 6. A solid dispersion according to claim1, wherein said polymer comprises EUDRAGIT® L 100-55.
 7. A soliddispersion according to claim 1, wherein the ratio of the amount byweight of Compound I within the solid dispersion to the amount by weightof the ionic polymer therein is from about 1:9 to about 1:1.
 8. A soliddispersion according to claim 1, wherein the ratio of the amount byweight of Compound I within the solid dispersion to the amount by weightof the ionic polymer therein is from about 2:8 to about 4:6.
 9. A soliddispersion according to claim 1, wherein the ratio of the amount byweight of Compound I within the solid dispersion to the amount by weightof the ionic polymer therein is about 3:7.
 10. A solid dispersionaccording to claim 1, wherein Compound I is primarily in amorphous form.11. A solid dispersion according to claim 4, wherein hydroxypropylmethylcellulose acetate succinate (HPMCAS) is present in an amount of not lessthan about 20%, by weight, of the solid dispersion.
 12. A soliddispersion according to claim 11, wherein hydroxypropylmethyl celluloseacetate succinate is present in an amount of from about 20% to about 95%by weight of the solid dispersion.
 13. A solid dispersion according toclaim 11, wherein hydroxypropylmethyl cellulose acetate succinate ispresent in an amount of about 20% to about 70% by weight of the soliddispersion.
 14. A formulation comprising the solid dispersion accordingto claim 1 suspended in an aqueous vehicle.
 15. A formulation accordingto claim 14 further comprising colloidal silicon dioxide.
 16. Aformulation according to claim 15, wherein said colloidal silicondioxide is present in an amount of at least 0.5% by weight of theformulation.
 17. A formulation according to claim 16, wherein saidaqueous vehicle contains 2% by weight hydroxypropylcellulose.
 18. Acomposition comprising a solid dispersion according to claim 1, and apharmaceutically-acceptable carrier.
 19. A formulation comprising thecomposition according to claim 18 suspended in an aqueous vehicle.
 20. Aformulation according to claim 19 further comprising colloidal silicondioxide.
 21. A formulation according to claim 20, wherein said colloidalsilicon dioxide is present in an amount of at least 0.5% by weight ofthe formulation.
 22. A formulation according to claim 19, wherein saidaqueous vehicle contains 2% by weight hydroxypropylcellulose.
 23. Amethod for making a solid dispersion according to claim 1, said methodcomprising microprecipitating Compound I and an ionic polymer.
 24. Amethod according to claim 23, wherein Compound I and the ionic polymersimultaneously precipitate out to form a molecular dispersion ofCompound I in said ionic polymer.
 25. A method according to claim 23,wherein the solid dispersion is prepared by spray drying.
 26. A methodaccording to claim 23, wherein the solid dispersion is prepared by hotmelt extrusion.
 27. A method according to claim 23, wherein said methodcomprises the method step of a solvent controlled precipitation.
 28. Amethod according to claim 23, wherein said polymer ishydroxypropylmethyl cellulose acetate succinate.
 29. A method accordingto claim 28, wherein Compound I and hydroxypropylmethyl celluloseacetate succinate are dissolved in an organic solvent.
 30. A methodaccording to claim 29, wherein said solvent is selected from the groupconsisting of dimethylformamide, dimethylacetamide, dimethyl sulfoxide,and N-methylpyrrolidone.
 31. A method according to claim 29, wherein theresulting solution is added into water, whereby Compound I andhydroxypropylmethyl cellulose acetate succinate simultaneouslyprecipitate out to form a solid molecular complex containing Compound Iembedded in a matrix formed by said polymer.
 32. A method according toclaim 29, wherein the resulting solution is added into aqueoushydrochloric acid (HCl), whereby Compound I and hydroxypropylmethylcellulose acetate succinate simultaneously precipitate out to form asolid molecular complex containing Compound I embedded in a matrixformed by said polymer.
 33. A method according to claim 23, wherein theresulting solid molecular complex is washed with water to remove theorganic solvent.
 34. A method according to claim 23, comprising thefollowing steps: (a) dissolution of Compound I and HPMCAS in the sameorganic solvent to give one single organic phase; (b) continuouslyadding the organic phase obtained under (a) into an aqueous phase whichis present in a mixing chamber, said mixing chamber being equipped witha high shear mixing unit and two additional openings which connect saidmixing chamber to a closed loop wherein said aqueous phase is circulatedand passes through the mixing chamber; (c) precipitation of a mixtureconsisting of the amorphous form of Compound I and HPMCAS out of theaqueous phase mentioned under (b), while the high shear mixer isoperating and said aqueous phase is passed through the mixing chamber ina closed loop, resulting in the formation of an aqueous suspension ofthe precipitate; (d) continuously circulating the aqueous suspensionthrough the mixing chamber while the high shear mixing unit is operatingand after the organic solution prepared under (a) has been completelyadded to the aqueous phase until a defined particle size and/or particlesize distribution is obtained; (e) isolating the solid phase from thesuspension; (f) washing the isolated solid phase with water; and (g)delumping and drying the solid phase.
 35. A method according to claim34, wherein the organic phase in (a) is a 35% solution of Compound I andHPMCAS in DMA, the ratio of Compound I to HPMCAS being 30% to 70% (w/w);and the continuous adding in step (b) is achieved via an injector nozzlewhich is oriented at an angle between 40 and 50° to the longitudinalaxis of the high shear mixer and has a distance of about 1 to about 10mm from the rotor of said high shear mixer which is operating with a tipspeed of about 15 to about 25 m/sec.
 36. A crystalline polymorph Form 1of Compound I that exhibits a powder x-ray diffraction pattern havingcharacteristic peak locations of approximately 4.7, 9.4, 11.0, 12.5, and15.4 degrees 2θ.
 37. A crystalline polymorph according to claim 36,wherein said polymorph exhibits a powder x-ray diffraction patternhaving characteristic peak locations of approximately 4.7, 9.4, 10.0,11.0, 12.5, 14.2, 15.4, 18.6, and 22.2 degrees 2θ.
 38. A crystallinepolymorph according to claim 36, wherein said polymorph exhibits apowder x-ray diffraction pattern having characteristic peak locations ofapproximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 16.1, 18.6, 19.0,22.2 and 26.8 degrees 2θ.
 39. A crystalline polymorph according to claim36, wherein said polymorph exhibits a powder x-ray diffraction patternsubstantially the same as the powder x-ray diffraction pattern ofFIG.
 1. 40. A method according to claim 23, wherein Compound I is acrystalline polymorph that exhibits a powder x-ray diffraction patternhaving characteristic peak locations of approximately 4.7, 9.4, 11.0,12.5, and 15.4 degrees 2θ.
 41. A purified form of the crystallinepolymorph of claim
 36. 42. A crystalline polymorph Form 2 of Compound Ithat exhibits a powder x-ray diffraction pattern having characteristicpeak locations of approximately 8.8, 9.2, 13.5, 19.1 and 24.4 degrees2θ.
 43. A crystalline polymorph according to claim 42, wherein saidpolymorph exhibits a powder x-ray diffraction pattern havingcharacteristic peak locations of approximately 6.7, 8.8, 9.2, 13.5,15.0, 17.7, 19.1, 19.7, 21.4 and 24.4 degrees 2θ.
 44. A crystallinepolymorph according to claim 42, wherein said polymorph exhibits apowder x-ray diffraction pattern having characteristic peak locations ofapproximately 6.7, 8.8, 9.2, 13.5, 14.1, 14.5, 15.0, 16.2, 17.0, 17.7,19.1, 19.7, 21.4, 22.2, 24.1, 24.4, and 28.1 degrees 2θ.
 45. Acrystalline polymorph according to claim 42, wherein said polymorphexhibits a powder x-ray diffraction pattern substantially the same asthe powder x-ray diffraction pattern of FIG.
 2. 46. A method accordingto claim 23, wherein Compound I is a crystalline polymorph that exhibitsa powder x-ray diffraction pattern having characteristic peak locationsof approximately 8.8, 9.2, 13.5, 19.1 and 24.4 degrees 2θ.
 47. Apurified form of the crystalline polymorph of claim
 42. 48. Acomposition comprising an amorphous form of Compound I.
 49. A mesylatesalt of Compound I.
 50. A tosylate salt of Compound I.
 51. A maleatesalt of Compound I.
 52. An oxalate salt of Compound I.
 53. Adichloroacetate salt of Compound I.